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Welcome to the Clinical
Center Grand Rounds,

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a weekly series of educational
lectures for physicians and

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health care professionals
broadcast from the Clinical

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Center at the National
Institutes of Health in

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Bethesda, MD.

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The NIH Clinical Center is the
world's largest hospital totally

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dedicated to investigational
research and leads the global

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effort in training today's
investigators and discovering

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tomorrow's cures.

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Learn more by visiting us online
at http://clinicalcenter.nih.gov

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TODAY WE WELCOME OUR SPEAKERS,

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DR. DEREK NARENDRA AND CHIEF OF

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THE INHERITED MOVEMENT DISORDERS

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UNIT, AND DR. CLAIRE LE PICHON,

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DIVISION OF INTRAMURAL RESEARCH

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IN THE EUNICE KENNEDY SHRIVER

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NATIONAL INSTITUTE OF CHILD

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HEALTH AND HUMAN DEVELOPMENT.

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DR. NARENDRA EARNED HIS BACHELOR

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FROM COLUMBIA UNIVERSITY, AND

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MEDICAL DEGREE FROM THE

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UNIVERSITY OF MICHIGAN.

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THROUGH HIS GRADUATE RESEARCH,

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HE IDENTIFIED A NOVEL MITOPHAGY

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PATHWAY THROUGH THE COORDINATED

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ACTIVITIES OF PARKIN AND PINK1,

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MUTATIONS WHICH ARE THE LEADING

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CAUSE OF EARLY ONSET PARKINSON'S

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DEED.

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DISEASE.

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COMPLETED NEUROLOGY RESIDENCY

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TRAINING AT THE BRIGHAM AND

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WOMEN'S HOSPITAL AND

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MASSACHUSETTS GENERAL HOSPITAL

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HARVARD PROGRAM IN 2016, WITH

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ADDITIONAL FELLOWSHIP TRAINING

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OF MOVEMENT DISORDERS AT

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UNIVERSITY OF PENNSYLVANIA.

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IN 2017, DR. NARENDRA RECEIVED

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THE TRANSITION TO INDEPENDENCE

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AWARD AND JOINED NINDS AS A

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CLINICAL -- ASSISTANT CLINICAL

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INVESTIGATOR WITHIN THE

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NEUROGENETICS BRANCH.

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HIS LABORATORY FOCUSES ON

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MITOCHONDRIAL DYSFUNCTION AND

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STRESS RESPONSES IN DISORDERS

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SUCH AT PARKINSON'S DISEASE,

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ALS.

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IN 2020 HE RECEIVED A LASKER

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CLINICAL RESEARCH SCHOLARSHIP

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AND BECAME A TENURE TRACK

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INVESTIGATOR.

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DRTHE MOVEMENT DISORDER SOCIETY

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AND AMERICAN NEUROLOGICAL

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ASSOCIATION AND IN 2022, HE

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RECEIVED AN AWARD IN

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NEUROSCIENCE.

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OUR SECOND SPEAKER IS DR. CLAIRE

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LE PICHON.

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DR. LE PICHON EARNED HER

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BACCALAUREATE FROM UNIVERSITY OF

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CAMBRIDGE IN THE UNITED KINGDOM

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AND HER PH.D. IN BIOLOGICAL

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SCIENCES FROM COLUMBIA

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UNIVERSITY IN 2007.

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AT COLUMBIA, IN A LABORATORY OF

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DR. STUART FIRESTEIN, SHE

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DEVELOPED HER INTEREST IN

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NEURODEGENERATIVE DISEASE WHILE

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STUDYING THE FUNCTION OF THE

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CELLULAR PRION PROTEIN, PRPC.

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AFTER HER GRADUATE STUDIES,

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DR. LE PICHON JOINED GENERAL

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TECHGENENTECH,PRE-CLINICAL DRUGT

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FOR NEURODEGENERATIVE DISEASES.

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IN 2013, SHE JOINED THE NATIONAL

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INSTITUTE OF NEUROLOGICAL

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DISORDERS AND STROKE AS A SENIOR

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RESEARCH FELLOW AND IN 2016, SHE

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WAS INVITED TO BECOME A TENURE

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TRACK INVESTIGATOR IN NICHD.

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DR. LE PICHON'S LABORATORY

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EMPLOYS A MULTIDISCIPLINARY

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APPROACH USING MOUSE MODELS AND

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HUMAN IPSC-DERIVED NEURONS TO

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INVESTIGATE THE EARLY EVENTS

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UNDERLYING THE ONSET AND

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PROGRESSION OF NEURODEGENERATIVE

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DISEASE.

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DR. LE PICHON EARNED THE NIH'S

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DIRECTOR'S AWARD, THE

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KIRSCHSTEIN AWARD FOR MENTORING

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IN 2021, AND RECEIVED NUMEROUS

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NICHD SCIENTIFIC DIRECTORS

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AWARDS AND MERIT AWARDS.

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SHE IS A MEMBER OF THE AMERICAN

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SOCIETY FOR CELL BIOLOGY AND

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SOCIETY FOR NEURAL SCIENCE AND

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IS A NATIONALLY AND

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INTERNATIONALLY RECOGNIZED

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SPEAKER IN THE FIELD OF

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NEURODEGENERATIVE DISEASES.

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PLEASE WELCOME OUR FIRST

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SPEAKER, DR. NARENDRA, LESSONS

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FROM GENETICS.

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WELL, THANK YOU FOR THAT

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INTRODUCTION AND FOR THE

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OPPORTUNITY TO SHARE WORK THAT

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OUR GROUP HAS BEEN DOING OVER

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THE LAST FIVE YEARS FOCUSED ON

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MITOCHONDRIA AND HOW DYSFUNCTION

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CAN LEAD TO NEURODEGENERATION

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AND HOW THE CELERY SP CELL RESPO

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DAMAGED MITOCHONDRIA.

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THESE ARE MY DISCLOSURES, THAT I

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WON'T BE TALKING ABOUT TODAY.

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IT'S NOT PERHAPS SURPRISING THAT

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MITOCHONDRIAL FUNCTION CAN BE A

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DRIVER OF NEURODEGENERATION

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GIVEN THAT THE NEURONS AND

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MYOSITES HAVE VERY HIGH RG

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DEMANDS.

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THE WAY THEY'RE ABLE TO DO THAT

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IS THROUGH THESE MITOCHONDRIA

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THAT CAN PROVIDE ATP IN ORDER TO

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MAINTAIN THOSE CONTRACTIONS.

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THESE MITOCHONDRIA HAVE TO NOT

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ONLY BE PROPERLY FUNCTIONING BUT

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THEY ALSO HAVE TO BE PROPERLY

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SHAPED AND DISTRIBUTED IN THE

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TISSUE TO MEET THAT ENERGY

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DEMAND.

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SIMILARLY IF YOU THINK ABOUT THE

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NEURONS, SPINAL CORD AND

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ELSEWHERE, THEY HAVE VERY HIGH

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LOCAL DEMANDS FOR ATP SUCH AS AT

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THE SNAPS HERE.

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SYNAPSE HERE.THESE ARE ALSO MITD

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TEND TO ACCUMULATE MITOCHONDRIAL

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DAMAGE OVER THE NORMAL COURSE OF

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AGING, TO A GREATER EXTENT THAN

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MITOTIC CELLS THROUGH CELL

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DIVISION.

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THESE CELLS ESPECIALLY ARE

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DEPENDENT ON MECHANISMS THAT

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ALLOW THE CELL TO BE ABLE TO

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RECOGNIZE WHEN MITOCHONDRIAL

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DAMAGE HAS OCCURRED AND TO BE

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ABLE TO RESPOND TO THAT

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MITOCHONDRIAL DAMAGE.

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YOU MIGHT IMAGINE A COUPLE OF

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DIFFERENT STRATEGIES THAT THE

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CELL MIGHT USE.

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ONE MIGHT BE TO ALLOW THE CHANGE

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IN MITOCHONDRIA TO LEAD TO A

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CHANGE IN THE OVERALL CELLULAR

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STATE AND THEN SINCE THAT CHANGE

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IN CELLULAR STATE -- THIS SEEMS

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TO BE HOW THE CELE CELL RESPONDH

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AS IN ATP THAT ARE VERY

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DEPENDENT ON MITOCHONDRIAL

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FUNCTION IN THE CELL.

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YOU MIGHT IMAGINE THAT THERE

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MIGHT BE ANOTHER STRATEGY,

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THOUGH, IF THERE'S A SENSOR OF

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THAT MITOCHONDRIAL DAMAGE WITHIN

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THE MITOCHONDRIA ITSELF, THAT

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MIGHT SERVE AS A WAY OF

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RECOGNIZING WHEN THAT BECOMES

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DAMAGED AND ALLOW THE CELL TO

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RESPOND TO THAT DAMAGE, CONTAIN

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IT BEFORE IT LEADS TO A CHANGE

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IN THE OVERALL CELLULAR STATE.

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BUT THERE ARE MECHANISMS THAT

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ARE ABLE TO DO THIS, PERHAPS THE

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BEST DESCRIBED ONE OF WHICH IS

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THIS PINK1 PARKIN AUTOPHAGY

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PATHWAY.

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THE WAY THIS PATHWAY WORKS IS MY

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TMITOCHONDRIA UNDERGOES SOME SOT

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OF DAMAGE, NORMALLY IMPORTED TO

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THE -- IF THAT MITOCHONDRIA IS

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DAMAGED AND IMPORT PATH IS

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BLOCKED THEN PINK1 ACCUMULATES

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INSTEAD ON THE OUTER.

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PINK1 IS A KINASE AND IT WILL

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ACTIVATE PARKIN, WHICH WILL THEN

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EU BIC TI NATE PROTEINS ON THE

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OUTER MEMBRANE.

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THIS SERVES AS A WAY OF MARKING

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THIS DAMAGED MITOCHONDRION AND

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DELIVERY TO A LYSOSOME WHERE IT

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CAN BE DEGRADED.

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THIS ACTS AS A CLEAN-UP PATHWAY

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FOR DAMAGED MITOCHONDRION IN THE

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CELL AND BECAUSE RECESSIVE

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MUTATIONS ARE THE LEADING

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GENETIC CAUSE OF EARLY ONSET

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PARKINSON'S DISEASE, IT ALSO

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IMPLICATES THIS MITOCHONDRIA

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CONTROL PATHWAY IN PARKINSON'S

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AS WELL AS OTHER FORMS OF KNEW

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OWE DEGENERATION.

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IN ADDITION TO THIS MI TO HAVE

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 -- INTO THEHEALTHY MITOCHONDRIE

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CELL.

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MITOCHONDRIA NORMALLY UNDERGO

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THESE SI CYCLES OF FUSION AND

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DIVISION AND THESE ARE MEDIATED

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BY A SET OF GTP ACES ON THE

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OUTER MEMBRANE, YOU GET FUSION

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OF THAT MEMBRANE AND THE INNER

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MEMBRANE IS MEDIATED BY FEW

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SHON -- IS MADE BY OMA1 THEN THE

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MY TOE COULMITOCHONDRIA -- CALLT

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ALLOWS THAT MITOCHONDRIA TO

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SPLIT AGAIN.

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THROUGH THESE CYCLES OF FUSION

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AND DIVISION THE CELL IS ABLE TO

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CHANGE THE SHAPE OF THE

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MITOCHONDRIAL NETWORK DYNAMIC

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FULLY IN RESPONSE TO CERTAIN

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DEVELOPMENTAL OR METABOLIC

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QUEUES AND IT ALSO ALLOWS THE

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CELL TO MAINTAIN QUALITY OF THE

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OVERALL MITOCHONDRIAL -- BUT IF

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THE M MITOCHONDRION UNDERGOES

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DAMAGE YOU DON'T WANT TO FUSE

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ANYMORE, IT DEGRADES THESE

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FUSION PROTEINS ON THE OUTER

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MEMBRANE, THEN CLEAVES THE

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OMA1 FROM THE INNER MEMBRANE.

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IT DOES THIS THROUGH AT LEAST

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TWO DIFFERENT MECHANISMS.

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ONE DEPENDS ON THE PINK1 PARKIN

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PATHWAY ON THE OUTER MEMBRANE,

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AND EVEN AT LOW LEVELS OF PARKIN

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YOU'LL SEE UBIQUINIATION AND

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DEGRADATION.

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THERE'S A PARALLEL PATHWAY THAT

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OCCURS ON THE INNER MEMBRANE OF

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THE MITOCHONDRION, WHERE INSTEAD

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OF PINK1 ACTING AS THE SENSOR OF

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MITOCHONDRIAL DAMAGE, YOU HAVE

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OMA1 WHICH IS ABLE TO SENSE

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DAMAGE OF THIS INNER MEMBRANE.

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IT BECOMES MORE ACTIVE AND WILL

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CLEAVE THE LONG FORM OF OPA1 TO

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SHORT FORM.

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THE SHORT FORM OF OPA1 CAN'T

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MEDIATE FUSION ON ITS OWN SO

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THIS INHIBITS FUSION SO YOU HAVE

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THESE TWO DIFFERENT SENSORS OF

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MITOCHONDRIAL DAMAGE, PINK1

256
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WORKING ON THE OUTER MEMBRANE

257
00:09:48,040 --> 00:09:49,360
AND ONE THAT WORKS ON THE INNER

258
00:09:49,360 --> 00:09:50,120
MEMBRANE.

259
00:09:50,120 --> 00:09:51,200
THE OVERALL INTEREST OF OUR

260
00:09:51,200 --> 00:09:53,080
RESEARCH GROUP IS TO TRY TO

261
00:09:53,080 --> 00:09:55,800
UNDERSTAND THESE MECHANISMS OF

262
00:09:55,800 --> 00:09:58,040
CELL SENSING OF MITOCHONDRIAL

263
00:09:58,040 --> 00:09:59,960
DAMAGE AND THE ROLE THEY PLAY IN

264
00:09:59,960 --> 00:10:00,840
NEURODEGENERATION AND HOW THEY

265
00:10:00,840 --> 00:10:03,360
MIGHT BE MODULATED TO HELP TREAT

266
00:10:03,360 --> 00:10:06,760
NANEURODEGENERATIVE DISORDERS.

267
00:10:06,760 --> 00:10:09,160
OUR LAB FOCUS ON THIS PINK1

268
00:10:09,160 --> 00:10:10,680
PARKIN PATHWAY AS SENSOR OF THE

269
00:10:10,680 --> 00:10:13,080
DAMAGE AND ITS ROLE IN

270
00:10:13,080 --> 00:10:14,800
PARKINSON'S DISEASE, AND THE

271
00:10:14,800 --> 00:10:17,120
SECOND IS TO REALLY FOCUS ON

272
00:10:17,120 --> 00:10:19,760
THIS OMA1 PATHWAY THAT WE FOUND

273
00:10:19,760 --> 00:10:23,160
IS VERY STRONGLY ACTIVATED BY

274
00:10:23,160 --> 00:10:25,440
MUTATIONS IN TWO OTHER

275
00:10:25,440 --> 00:10:26,760
MITOCHONDRIAL PROTEINS THAT LEAD

276
00:10:26,760 --> 00:10:28,640
TO DIFFERENT FORMS OF

277
00:10:28,640 --> 00:10:29,760
NEURODEGENERATION.

278
00:10:29,760 --> 00:10:30,800
AND THEN THE FOCUS OF TODAY'S

279
00:10:30,800 --> 00:10:38,560
TALK WILL BE ON A SPECIFIC

280
00:10:38,560 --> 00:10:40,760
MUTATION, CHCHD10 AND HOW THAT

281
00:10:40,760 --> 00:10:42,080
PARTICULAR MUTATION HAS LED US

282
00:10:42,080 --> 00:10:43,400
TO RECOGNIZE THE IMPORTANCE OF

283
00:10:43,400 --> 00:10:45,880
THIS OMA1 STRESS RESPONSE,

284
00:10:45,880 --> 00:10:47,440
PARTICULARLY IN VIVO.

285
00:10:47,440 --> 00:10:49,960
SO I'LL TELL YOU -- INTRODUCE

286
00:10:49,960 --> 00:10:54,000
THIS PROTEIN A LITTLE BIT MORE,

287
00:10:54,000 --> 00:10:56,080
THEY'RE SMALL PROTEINS WITHIN

288
00:10:56,080 --> 00:10:58,360
THE INTERMEMBRANE SPACE OF THE

289
00:10:58,360 --> 00:10:58,880
MITOCHONDRIA.

290
00:10:58,880 --> 00:11:00,560
SO MITOCHONDRIA HAVE THIS OUTER

291
00:11:00,560 --> 00:11:01,880
MEMBRANE AS WELL AS THIS INNER

292
00:11:01,880 --> 00:11:04,040
MEMBRANE AND THESE PROTEINS ARE

293
00:11:04,040 --> 00:11:05,600
LOCATED BETWEEN THOSE TWO

294
00:11:05,600 --> 00:11:06,720
MEMBRANES IN THE SPACE.

295
00:11:06,720 --> 00:11:13,600
INNER MEMBRANE WILL ALSO FORM

296
00:11:13,600 --> 00:11:15,000
MITOCHONDRIAL -- THESE PROTEINS

297
00:11:15,000 --> 00:11:18,480
WILL EXTEND DOWN INTO THOSE

298
00:11:18,480 --> 00:11:19,360
MITOCHONDRIAL CHRISTY AND IT

299
00:11:19,360 --> 00:11:22,440
SEEMS THAT THEY'RE IMPORTED FOR

300
00:11:22,440 --> 00:11:23,520
MAINTAINING NORMAL STRUCTURE AS

301
00:11:23,520 --> 00:11:27,400
WELL AS FOR MAINTAINING OPTIMAL

302
00:11:27,400 --> 00:11:31,520
CAPACITY OF THE MITOCHONDRIA.

303
00:11:31,520 --> 00:11:33,480
WE'VE SHOWN THESE PROTEINS ARE

304
00:11:33,480 --> 00:11:34,520
FUNCTIONING WITH ONE ANOTHER AND

305
00:11:34,520 --> 00:11:37,640
IF YOU KNOCK OUT EITHER ALONE IN

306
00:11:37,640 --> 00:11:38,960
THE MOUSE IT DOESN'T RESULT OF

307
00:11:38,960 --> 00:11:40,560
MUCH OF A PHENOTYPE BUT IF YOU

308
00:11:40,560 --> 00:11:42,440
FLOCK OUT BOTH OF THESE PROTEINS

309
00:11:42,440 --> 00:11:50,120
TOGETHER, THE MICE DEVELOP A

310
00:11:50,120 --> 00:11:51,320
CARDIOMYOPATHY.

311
00:11:51,320 --> 00:11:53,400
ADDITIONALLY IF YOU LOOK IN THE

312
00:11:53,400 --> 00:11:54,400
HEART TISSUE YOU SEE STRESS

313
00:11:54,400 --> 00:11:55,440
RESPONSE THAT I'LL GO INTO MORE

314
00:11:55,440 --> 00:11:57,120
DETAIL IN A MINUTE.

315
00:11:57,120 --> 00:11:59,520
WE KNOCK OUT BOTH OF THESE

316
00:11:59,520 --> 00:12:00,840
PROTEINS BUT YOU DON'T SEE IF

317
00:12:00,840 --> 00:12:02,680
YOU KNOCK OUT ONLY ONE ALONE SO

318
00:12:02,680 --> 00:12:04,440
THEY SEEM TO BE DOING SOMETHING

319
00:12:04,440 --> 00:12:11,120
TOGETHER ON THE CELL.

320
00:12:11,120 --> 00:12:16,360
DOMINANT MUTATIONS IN CHCHD10

321
00:12:16,360 --> 00:12:17,760
CAUSE NEUROMUSCULAR DISORDERS.

322
00:12:17,760 --> 00:12:20,560
THIS RANGES FROM DEMENTIA, ALS,

323
00:12:20,560 --> 00:12:22,040
DESCRIBED WITH THE ORIGINAL

324
00:12:22,040 --> 00:12:28,160
MUTATION IN THE TWO FAMILIES

325
00:12:28,160 --> 00:12:30,840
THESE FAMILIES HAVE A VERY

326
00:12:30,840 --> 00:12:31,720
COMPLEX NEUROLOGICAL PHENOTYPE

327
00:12:31,720 --> 00:12:33,440
WHERE THEY HAVE INVOLVEMENT OF

328
00:12:33,440 --> 00:12:34,880
MUSCLE AS WELL AS SPINAL CORD AS

329
00:12:34,880 --> 00:12:35,640
WELL AS THE BRAIN.

330
00:12:35,640 --> 00:12:39,640
THERE'S A MUCH MORE LIMITED

331
00:12:39,640 --> 00:12:40,880
PHENOTYPE THAT CAN BE SEEN WITH

332
00:12:40,880 --> 00:12:42,160
ANOTHER MUTATION WHERE JUST THE

333
00:12:42,160 --> 00:12:43,320
LOWER MOTOR NEURONS IN THE

334
00:12:43,320 --> 00:12:44,800
SPINAL CORD ARE AFFECTED,

335
00:12:44,800 --> 00:12:46,680
CAUSING AN ADULT ONSET FORM OF

336
00:12:46,680 --> 00:12:47,960
SPINAL MUSCULAR ATROPHY.

337
00:12:47,960 --> 00:12:49,840
THIS IS RELATIVELY COMMON IN

338
00:12:49,840 --> 00:12:51,000
SOUTHEAST FINLAND.

339
00:12:51,000 --> 00:12:52,440
THERE'S ANOTHER MUTATION THAT'S

340
00:12:52,440 --> 00:12:56,400
PROBABLY THE MOST COMMON CHCHD10

341
00:12:56,400 --> 00:12:58,240
MUTATION IN NORTH AMERICA WHERE

342
00:12:58,240 --> 00:13:00,640
IT CAUSES MORE OF A TYPICAL ALS

343
00:13:00,640 --> 00:13:02,400
PHENOTYPE, ALTHOUGH THESE

344
00:13:02,400 --> 00:13:04,240
PATIENTS ARE SLOWLY PROGRESSIVE.

345
00:13:04,240 --> 00:13:07,760
IN COLLABORATION WITH NCATS WHO

346
00:13:07,760 --> 00:13:10,000
IDENTIFIED THIS MUTATION, WE ARE

347
00:13:10,000 --> 00:13:11,680
DEVELOPING AN ANTI -- TO TRY TO

348
00:13:11,680 --> 00:13:13,240
TREAT THIS FORM OF ALS.

349
00:13:13,240 --> 00:13:14,760
WE SAW A COUPLE OF PATIENTS WITH

350
00:13:14,760 --> 00:13:16,960
THIS FORM OF ALS IN THE CLINICAL

351
00:13:16,960 --> 00:13:18,800
CENTER EARLIER THIS YEAR.

352
00:13:18,800 --> 00:13:21,560
THEN THERE'S ANOTHER MUTATION

353
00:13:21,560 --> 00:13:22,400
WHERE THE INDIVIDUALS WILL

354
00:13:22,400 --> 00:13:24,400
DEVELOP JUST A DOMINANT FORM OF

355
00:13:24,400 --> 00:13:26,360
MYOPATHY AND AS I'LL SHOW YOU IN

356
00:13:26,360 --> 00:13:27,960
A SECOND ALSO CARDIOMYOPATHY BUT

357
00:13:27,960 --> 00:13:31,800
THEY DON'T SEEM TO HAVE MOTOR

358
00:13:31,800 --> 00:13:33,120
NEURONS, THE SPINAL CORD SEEMS

359
00:13:33,120 --> 00:13:34,040
TO BE SPARED.

360
00:13:34,040 --> 00:13:35,440
IT'S INTERESTING CAN YOU HAVE

361
00:13:35,440 --> 00:13:36,200
TWO MUTATIONS THAT ARE NEXT TO

362
00:13:36,200 --> 00:13:38,400
EACH OTHER THAT CAN HAVE VERY

363
00:13:38,400 --> 00:13:40,440
DIFFERENT PHENOTYPIC

364
00:13:40,440 --> 00:13:40,840
MANIFESTATIONS.

365
00:13:40,840 --> 00:13:41,800
ONE THING THAT HAD BEEN UNCLEAR

366
00:13:41,800 --> 00:13:43,680
IN THE FIELD WAS EXACTLY WHICH

367
00:13:43,680 --> 00:13:46,680
MUTATION IS THE CAUSE OF THE

368
00:13:46,680 --> 00:13:48,320
MUTATION FOR THIS DOMINANT FORM

369
00:13:48,320 --> 00:13:48,920
OF MYOPATHY.

370
00:13:48,920 --> 00:13:50,120
THE REASON THAT WAS UNCLEAR IS

371
00:13:50,120 --> 00:13:53,920
THAT ALTHOUGH -- IN THE LAB AT

372
00:13:53,920 --> 00:13:56,560
NORTHWESTERN WAS ABLE TO

373
00:13:56,560 --> 00:13:58,600
IDENTIFY CHCHD10 AS THE

374
00:13:58,600 --> 00:14:00,480
CAUSATIVE GENE BY POSITIONAL

375
00:14:00,480 --> 00:14:01,960
CLONING, THEY FOUND OUT ONE

376
00:14:01,960 --> 00:14:03,480
VARIANT BUT ACTUALLY TWO

377
00:14:03,480 --> 00:14:03,840
VARIANTS.

378
00:14:03,840 --> 00:14:06,200
SO THEY COULDN'T SAY BASED ON

379
00:14:06,200 --> 00:14:09,560
GENETIC GROUNDS ALONE FROM THIS

380
00:14:09,560 --> 00:14:11,160
ONE FAMILY THESE TWO MUTATIONS

381
00:14:11,160 --> 00:14:12,280
WAS THE CAUSE OF THE MUTATION.

382
00:14:12,280 --> 00:14:13,840
SO THIS WAS IN THE BACK OF MY

383
00:14:13,840 --> 00:14:17,760
MIND WHEN I MET JEFF AT A

384
00:14:17,760 --> 00:14:19,400
CONFERENCE A FEW YEARS AGO WHO'S

385
00:14:19,400 --> 00:14:21,840
AN EXPERT IN MITOCHONDRIAL

386
00:14:21,840 --> 00:14:22,800
DISORDERS AT OXFORD.

387
00:14:22,800 --> 00:14:24,200
SHE MENTIONED SHE'D BEEN

388
00:14:24,200 --> 00:14:25,320
FOLLOWING FOR A NUMBER OF YEARS

389
00:14:25,320 --> 00:14:27,800
A FAMILY THAT HAD A FORM OF

390
00:14:27,800 --> 00:14:29,360
CARDIOMYOPATHY AND THEY RECENTLY

391
00:14:29,360 --> 00:14:30,120
HAD DONE SEQUENCING AND

392
00:14:30,120 --> 00:14:34,280
IDENTIFIED THIS MUTATION IN

393
00:14:34,280 --> 00:14:35,440
CHCHD10 WITHOUT THE OTHER

394
00:14:35,440 --> 00:14:35,800
MUTATIONS.

395
00:14:35,800 --> 00:14:37,120
SO THIS WAS QUITE INTERESTING

396
00:14:37,120 --> 00:14:38,400
BECAUSE IT SUGGESTS THAT THIS IS

397
00:14:38,400 --> 00:14:39,640
PROBABLY THE CAUSE OF THE

398
00:14:39,640 --> 00:14:41,400
MUTATION FOR THIS DOMINANT FORM

399
00:14:41,400 --> 00:14:47,680
OF MYOPATHIES AND WE RESOLVED TO

400
00:14:47,680 --> 00:14:48,520
HELP CHARACTERIZE THIS TOGETHER

401
00:14:48,520 --> 00:14:49,640
AS PART OF THE COOPERATION.

402
00:14:49,640 --> 00:14:53,400
SO THIS IS SEEN AT 8 YEARS OLD,

403
00:14:53,400 --> 00:14:54,920
DISTAL AND PROXIMAL MUSCLE

404
00:14:54,920 --> 00:14:57,000
WASTING, ALSO SOME MILD FACIAL

405
00:14:57,000 --> 00:14:57,600
LUPUS.

406
00:14:57,600 --> 00:14:59,920
THIS IS HIM 12 YEARS LATER, AND

407
00:14:59,920 --> 00:15:01,280
AT THIS POINT HE'S HAD

408
00:15:01,280 --> 00:15:03,000
PROGRESSION OF THE MYOPATHY,

409
00:15:03,000 --> 00:15:03,560
WHEELCHAIR-BOUND.

410
00:15:03,560 --> 00:15:04,960
HE ALSO DEVELOPED A

411
00:15:04,960 --> 00:15:05,960
CARDIOMYOPATHY SEVERE ENOUGH TO

412
00:15:05,960 --> 00:15:09,360
REQUIRE A HEART TRANSPLANT.

413
00:15:09,360 --> 00:15:10,800
UNFORTUNATELY BECAUSE OF THE

414
00:15:10,800 --> 00:15:11,800
IMMUNOSUPPRESSION, HE DEVELOPED

415
00:15:11,800 --> 00:15:13,000
LYMPHOMA AND PASSED AWAY.

416
00:15:13,000 --> 00:15:14,760
THIS IS HIS FAMILY, HIS MOTHER

417
00:15:14,760 --> 00:15:16,760
HAD A VERY SIMILAR PHENOTYPE AND

418
00:15:16,760 --> 00:15:18,240
ALSO DIED YOUNG, AT THE AGE OF

419
00:15:18,240 --> 00:15:19,800
34, AND WE THINK THAT MOST

420
00:15:19,800 --> 00:15:22,520
LIKELY THIS WAS DUE TO A

421
00:15:22,520 --> 00:15:24,400
MUTATION IN HIS MOTHER.

422
00:15:24,400 --> 00:15:29,840
AT THIS POINT, PH.D. STUDENT IN

423
00:15:29,840 --> 00:15:31,080
THE LAB WAS INTERESTED IN TRYING

424
00:15:31,080 --> 00:15:32,280
TO BETTER UNDERSTAND THE

425
00:15:32,280 --> 00:15:33,320
PATHOGENESIS OF THIS DISORDER,

426
00:15:33,320 --> 00:15:35,880
SO WITH THE HELP OF NHLBI

427
00:15:35,880 --> 00:15:37,320
TRANSGENICS HE MADE A KNOCK-IN

428
00:15:37,320 --> 00:15:38,920
MOUSE MODEL WHERE HE INTRODUCED

429
00:15:38,920 --> 00:15:43,320
INTO THE MOUSE A GENE THAT WAS

430
00:15:43,320 --> 00:15:44,080
SEEN IN THE PATIENT.

431
00:15:44,080 --> 00:15:46,720
THESE HETEROZYGOUS MICE,

432
00:15:46,720 --> 00:15:48,040
DEVELOPED A PHENOTYPE THAT LOOKS

433
00:15:48,040 --> 00:15:50,840
VERY SIMILAR TO THE PATIENT'S

434
00:15:50,840 --> 00:15:52,640
PHENOTYPE, DECREASED SIZE AND

435
00:15:52,640 --> 00:15:55,320
WEIGHT, ALSO DECREASED STRENGTH

436
00:15:55,320 --> 00:15:57,760
AND MYOPATHY AND DECREASED HEART

437
00:15:57,760 --> 00:16:00,160
FUNCTION ON ECHO CARDIOGRAPHY.

438
00:16:00,160 --> 00:16:01,240
NOTABLY THIS PHENOTYPE IS

439
00:16:01,240 --> 00:16:02,240
DIFFERENT THAN WHAT WE HAD SEEN

440
00:16:02,240 --> 00:16:04,320
AND REPORTED FOR THE SINGLE

441
00:16:04,320 --> 00:16:06,080
KNOCKOUT MICE AS WELL AS THE

442
00:16:06,080 --> 00:16:07,680
DOUBLE KNOCKOUT MICE.

443
00:16:07,680 --> 00:16:09,240
AND THIS INDICATES THAT THIS

444
00:16:09,240 --> 00:16:12,640
MUTATION IS PROBABLY CAUSING

445
00:16:12,640 --> 00:16:14,280
DISEASE BY GAIN OF FUNCTION MOST

446
00:16:14,280 --> 00:16:16,800
LIKELY A TOXIC GAIN OF FUNCTION

447
00:16:16,800 --> 00:16:17,440
MECHANISM.

448
00:16:17,440 --> 00:16:19,280
IT ALSO HAS IMPLICATIONS FOR HOW

449
00:16:19,280 --> 00:16:20,640
WE'RE THINKING ABOUT TREATING

450
00:16:20,640 --> 00:16:21,480
THIS DISORDER BECAUSE IT MEANS

451
00:16:21,480 --> 00:16:23,880
IF YOU COULD LOWER LEVELS OF

452
00:16:23,880 --> 00:16:25,040
THIS TOXIC PROTEIN IT PROBABLY

453
00:16:25,040 --> 00:16:27,480
WOULD HAVE A THERAPEUTIC BENEFIT

454
00:16:27,480 --> 00:16:29,040
AND THE FACT THAT IT SEEMS TO BE

455
00:16:29,040 --> 00:16:30,640
TOLERATED AT LEAST IN MICE

456
00:16:30,640 --> 00:16:33,520
SUGGESTS THAT YOU CAN SAFELY

457
00:16:33,520 --> 00:16:36,800
LOWER EVEN -- LEVELS OF CHCHD10

458
00:16:36,800 --> 00:16:39,200
AND NOS HAVE A TOXICITY RESULT.

459
00:16:39,200 --> 00:16:42,040
WHAT HAPPENS TO THIS PROTEIN

460
00:16:42,040 --> 00:16:44,240
WHEN IT HAS THIS MUTATION, IT

461
00:16:44,240 --> 00:16:46,560
TENDS TO FORM FOCI, HEART MUSCLE

462
00:16:46,560 --> 00:16:47,600
SHOWN HERE, AND WE THINK THAT

463
00:16:47,600 --> 00:16:52,000
THESE FO FOCI ARE AGGREGATES OF0

464
00:16:52,000 --> 00:16:54,640
PROTEINS ACTUALLY LOCATED WITHIN

465
00:16:54,640 --> 00:16:55,520
THE MITOCHONDRIA.

466
00:16:55,520 --> 00:16:57,240
ALSO LOOKED AT NEIGHBORING

467
00:16:57,240 --> 00:17:00,840
MUTATION IN CHCHD10 AND OTHER

468
00:17:00,840 --> 00:17:01,720
KNOCK-IN MOUSE MODEL.

469
00:17:01,720 --> 00:17:04,360
THIS HAD BEEN PREVIOUSLY

470
00:17:04,360 --> 00:17:06,320
REPORTED TO ALSO HAVING A GATS

471
00:17:06,320 --> 00:17:10,920
TO HAVING AGATS THAT FORM IN THT

472
00:17:10,920 --> 00:17:12,720
MUSCLE.

473
00:17:12,720 --> 00:17:13,920
AGGREGATES WITH BOTH OF THESE

474
00:17:13,920 --> 00:17:15,440
MUTATIONS ARE DIFFERENT

475
00:17:15,440 --> 00:17:17,000
MORPHOLOGICALLY SO WITH THE G15R

476
00:17:17,000 --> 00:17:19,520
MUTATION THAT CAUSES THE SEVERE

477
00:17:19,520 --> 00:17:23,320
MYOPATHY, YOU HAVE THESE

478
00:17:23,320 --> 00:17:24,520
PUNCTATE-LIKE AGGREGATES WHEREAS

479
00:17:24,520 --> 00:17:28,240
YOU HAVE A DIFFERENT FORM OF

480
00:17:28,240 --> 00:17:34,840
AGGREGATE WITH A MILDER FORM OF

481
00:17:34,840 --> 00:17:36,240
MUSCLE INVOLVEMENT AND MORE

482
00:17:36,240 --> 00:17:37,320
SEVERE INVOLVEMENT OF MOTOR

483
00:17:37,320 --> 00:17:38,000
NEURONS.

484
00:17:38,000 --> 00:17:39,280
THE LOCALIZATION OF THESE

485
00:17:39,280 --> 00:17:40,280
AGGREGATES ALSO APPEARS TO BE

486
00:17:40,280 --> 00:17:40,600
DIFFERENT.

487
00:17:40,600 --> 00:17:43,560
SO WE CAN SEE THE BORDERS OF THE

488
00:17:43,560 --> 00:17:45,400
MITOCHONDRIA BY STAINING.

489
00:17:45,400 --> 00:17:46,640
THIS IS WHAT THEY LOOK LIKE IN

490
00:17:46,640 --> 00:17:52,560
THE HEALTHY WILD TYPE CONDITION,

491
00:17:52,560 --> 00:17:55,720
G58R, MAGENTA FOCI ARE LOCATED

492
00:17:55,720 --> 00:17:57,800
PREDOMINANTLY WITHIN THE

493
00:17:57,800 --> 00:17:58,720
MITOCHONDRIA, THE OTHERS ARE OUT

494
00:17:58,720 --> 00:18:00,280
OF THE MITOCHONDRIA.

495
00:18:00,280 --> 00:18:04,040
SO WHAT IS COMMON IS THEY'RE

496
00:18:04,040 --> 00:18:06,200
TOSSING C10 TO MISFOLD BUT

497
00:18:06,200 --> 00:18:08,480
PROBABLY IT FIST FOLDS INTO

498
00:18:08,480 --> 00:18:10,680
DIFFERENT TOXIC SPECIES AND

499
00:18:10,680 --> 00:18:11,800
PERHAPS THAT UNDERLIES THE

500
00:18:11,800 --> 00:18:12,760
DIFFERENT TISSUE VULNERABILITY

501
00:18:12,760 --> 00:18:16,040
TO THESE TOXIC PROTEINS.

502
00:18:16,040 --> 00:18:23,560
IT SEEMS THAT MISFOLDING OF

503
00:18:23,560 --> 00:18:25,600
CHCHD10 IS RELATED TO THESE TWO

504
00:18:25,600 --> 00:18:26,360
PROTEINS.

505
00:18:26,360 --> 00:18:32,280
TWO AUTOPSY CASES HAVE BEEN

506
00:18:32,280 --> 00:18:33,400
REPORTED, AND WHEN THEY LOOK IN

507
00:18:33,400 --> 00:18:41,160
THE AFFECTED REGION SUCH AS

508
00:18:41,160 --> 00:18:42,360
SUBSTANTIA NIGRA, INDICATING

509
00:18:42,360 --> 00:18:43,680
PROBABLY THIS PROTEIN IS

510
00:18:43,680 --> 00:18:44,520
MISFOLDING ALSO BECAUSE OF THIS

511
00:18:44,520 --> 00:18:45,200
MUTATION.

512
00:18:45,200 --> 00:18:46,600
SIMILARLY IN A CASE OF ALS

513
00:18:46,600 --> 00:18:48,720
THAT'S BEEN REPORTED DUE TO

514
00:18:48,720 --> 00:18:51,000
MUTATION IN CHCHD10, IN THE

515
00:18:51,000 --> 00:18:53,080
MOTOR NEURONS THAT ARE SURVIVING

516
00:18:53,080 --> 00:18:54,600
IN THE SPINAL CORD, YOU'LL

517
00:18:54,600 --> 00:18:57,000
FINDING A GATS OF CHCHD10 WITHIN

518
00:18:57,000 --> 00:18:59,600
THOSE MOTOR NEURONS THAT AREN'T

519
00:18:59,600 --> 00:19:03,440
TYPICALLY SEEN IN SPORADIC ALS.

520
00:19:03,440 --> 00:19:04,880
WE ALSO LOOKED ULTRA

521
00:19:04,880 --> 00:19:07,200
STRUCTURALLY AT THE MITOCHONDRIA

522
00:19:07,200 --> 00:19:10,440
TO SEE HOW THEY WERE AFFECTED BY

523
00:19:10,440 --> 00:19:12,080
THIS PROTEIN IN THE CENTER

524
00:19:12,080 --> 00:19:13,520
MEMBRANE SPACE.

525
00:19:13,520 --> 00:19:18,360
THE CHRISTY BEING VERY DISTORTED

526
00:19:18,360 --> 00:19:20,080
AS WELL AS THESE INTRACRYSTAL

527
00:19:20,080 --> 00:19:21,120
VESICLES THAT DEVELOP, SO WE

528
00:19:21,120 --> 00:19:23,480
THINK THIS MISFOLDED PROTEIN IS

529
00:19:23,480 --> 00:19:27,920
EXERTED STRESS ON THE INNER

530
00:19:27,920 --> 00:19:28,600
MEMBRANE -- MEMBRANE.

531
00:19:28,600 --> 00:19:31,160
AND IS LEADING TO WHAT'S

532
00:19:31,160 --> 00:19:32,760
ESSENTIALLY CHRISTYOPATHY, AND

533
00:19:32,760 --> 00:19:34,280
THE MILD DEFECTS WE SEE IN THE

534
00:19:34,280 --> 00:19:35,720
AFFECTED TISSUES ARE PROBABLY

535
00:19:35,720 --> 00:19:36,800
SECONDARY TO DAMAGE TO THIS

536
00:19:36,800 --> 00:19:37,240
INNER MEMBRANE.

537
00:19:37,240 --> 00:19:38,680
WE ALSO LOOKED AT THE OVERALL

538
00:19:38,680 --> 00:19:40,120
MORPHOLOGY OF THE MITOCHONDRIA

539
00:19:40,120 --> 00:19:44,160
IN THE HEART, USING A TECHNIQUE

540
00:19:44,160 --> 00:19:47,760
CALLED FIB SYN, THEY'RE

541
00:19:47,760 --> 00:19:48,720
PSEUDOCOLORRED AND YOU CAN SEE

542
00:19:48,720 --> 00:19:54,720
THE INDIVIDUAL MITOCHONDRIA, AND

543
00:19:54,720 --> 00:19:57,040
IF WE COMPARE THE CONTROL

544
00:19:57,040 --> 00:19:58,920
CONDITION AND WE FIND THE

545
00:19:58,920 --> 00:20:00,760
MITOCHONDRIA AND HEART ARE

546
00:20:00,760 --> 00:20:01,640
FRAGMENTED COMPARED TO THE

547
00:20:01,640 --> 00:20:02,520
CONTROL CONDITION AND OVERALL

548
00:20:02,520 --> 00:20:04,160
THE VOLUME OF THE MITOCHONDRIA

549
00:20:04,160 --> 00:20:05,360
IS ABOUT HALF OF WHAT WE SEE IN

550
00:20:05,360 --> 00:20:06,440
THE WILD TYPE CONDITION.

551
00:20:06,440 --> 00:20:08,120
SO THIS MITOCHONDRIAL

552
00:20:08,120 --> 00:20:09,520
FRAGMENTATION WAS REALLY

553
00:20:09,520 --> 00:20:10,800
DRAMATIC AND MADE US WONDER IF

554
00:20:10,800 --> 00:20:14,640
THIS MIGHT BE A -- PROCESS AND

555
00:20:14,640 --> 00:20:17,400
IN PARTICULAR IF IT MIGHT BE

556
00:20:17,400 --> 00:20:18,920
INDICATIVE OF THAT STRESS

557
00:20:18,920 --> 00:20:19,800
RESPONSE I INTRODUCED TO YOU AT

558
00:20:19,800 --> 00:20:22,320
THE BEGINNING WHEREBY

559
00:20:22,320 --> 00:20:25,840
DISRUPTIONS TO MEMBRANE --

560
00:20:25,840 --> 00:20:28,240
IDENTIFY THE INNER MEMBRANES ARE

561
00:20:28,240 --> 00:20:32,160
DISTORTED DUE TO THE PROTEIN

562
00:20:32,160 --> 00:20:34,000
MISFOLDING IN THE CHRISTY, TO

563
00:20:34,000 --> 00:20:35,760
ACTIVATED TO CLEAVE THE LONG

564
00:20:35,760 --> 00:20:37,520
FORMS TO THE SHORT FORMS.

565
00:20:37,520 --> 00:20:41,880
IF YOU INHIBIT FUSION

566
00:20:41,880 --> 00:20:43,600
FRAGMENTATION OF THE

567
00:20:43,600 --> 00:20:44,200
MITOCHONDRIAL NETWORKS.

568
00:20:44,200 --> 00:20:54,720
SO WE LOOKED AT OMA1 PROCESSING

569
00:20:55,680 --> 00:20:59,920
OF THE SPECIFIC OMA1, THE C AND

570
00:20:59,920 --> 00:21:02,960
E SHOWN IN THIS WESTERN BLOT

571
00:21:02,960 --> 00:21:05,840
WITH THE AFFECTED TISSUES.

572
00:21:05,840 --> 00:21:07,800
SIM SKELETAL MUSCLE, HEART

573
00:21:07,800 --> 00:21:10,440
TISSUE, WE SAW THE SAME PATTERN

574
00:21:10,440 --> 00:21:12,320
INDICATIVE OF OMA1 ACTIVATION.

575
00:21:12,320 --> 00:21:14,600
SO WE HAVE THIS OMA1 STRESS

576
00:21:14,600 --> 00:21:15,680
RESPONSE ACTIVATED BY THIS

577
00:21:15,680 --> 00:21:18,640
PROTEIN THAT'S MISFOLDING WITHIN

578
00:21:18,640 --> 00:21:19,200
MITOCHONDRIAL CRISTAE.

579
00:21:19,200 --> 00:21:20,280
SO WHILE WE WERE DOING THIS

580
00:21:20,280 --> 00:21:21,040
WORK, A COUPLE OF VERY

581
00:21:21,040 --> 00:21:23,120
INTERESTING PAPERS CAME OUT, ONE

582
00:21:23,120 --> 00:21:26,080
FROM UCSF AND ANOTHER IN MUNICH.

583
00:21:26,080 --> 00:21:28,080
WHAT THEY FOUND IS THAT AT LEAST

584
00:21:28,080 --> 00:21:29,360
IN CULTURED CELLS THAT ARE

585
00:21:29,360 --> 00:21:32,080
EXPOSED TO MITOCHONDRIAL TOXINS

586
00:21:32,080 --> 00:21:36,360
LIKE CCP AND -- OPA1 HAS ANOTHER

587
00:21:36,360 --> 00:21:38,520
SUBSTRATE IN ADDITION TO

588
00:21:38,520 --> 00:21:40,320
OPA1 CALLED DELI1.

589
00:21:40,320 --> 00:21:43,360
IT COMMUNICATES THE M

590
00:21:43,360 --> 00:21:44,560
MITOCHONDRIAL SUPPRESS BY

591
00:21:44,560 --> 00:21:46,800
OMA1 TO THE CYTOSOL NUCLEUS TO

592
00:21:46,800 --> 00:21:48,280
SOMETHING CALLED THE INTEGRATED

593
00:21:48,280 --> 00:21:50,800
STRESS RESPONSE.

594
00:21:50,800 --> 00:21:51,680
SPECIFICALLY OMA1 WILL CLEAVE

595
00:21:51,680 --> 00:21:54,000
THE LONG FORM OF DELE1 INTO A

596
00:21:54,000 --> 00:21:55,040
SHORT FORM THAT WILL THEN

597
00:21:55,040 --> 00:21:58,120
ACTIVATE THIS EIFT ALPHA CLIE

598
00:21:58,120 --> 00:21:58,560
NAIS.

599
00:21:58,560 --> 00:22:01,960
WHEN THIS EIF2L ALPHA IS

600
00:22:01,960 --> 00:22:03,480
PHOSPHORYLATED, THIS TRANSLATION

601
00:22:03,480 --> 00:22:04,160
INITIATION FACTOR IS GOING TO

602
00:22:04,160 --> 00:22:06,000
LEAD TO THE INTEGRATED STRESS

603
00:22:06,000 --> 00:22:07,200
RESPONSE THAT HAS TWO MAIN

604
00:22:07,200 --> 00:22:07,880
COMPONENTS.

605
00:22:07,880 --> 00:22:09,640
THE FIRST IS TO PUT A HALT ON

606
00:22:09,640 --> 00:22:11,360
MOST PROTEIN TRANSLATION SO YOU

607
00:22:11,360 --> 00:22:13,440
GET DECROSED PROTEIN SYNTHESIS

608
00:22:13,440 --> 00:22:15,760
OVERALL IN THE CELL.

609
00:22:15,760 --> 00:22:17,280
BUT THEN CERTAIN TRANSCRIPTION

610
00:22:17,280 --> 00:22:20,120
FACTORS LIKE ATF4 AND 5 THAT

611
00:22:20,120 --> 00:22:22,560
HAVE THESE SPECIAL UPSTREAM --

612
00:22:22,560 --> 00:22:23,960
ARE PREFERENTIALLY TRANSLATED AS

613
00:22:23,960 --> 00:22:25,160
YOU HAVE UPREGULATION OF THESE

614
00:22:25,160 --> 00:22:26,800
THAT CAN MEDIATE A

615
00:22:26,800 --> 00:22:27,480
TRANSCRIPTIONAL RESPONSE.

616
00:22:27,480 --> 00:22:28,760
IT'S CALLED THE INTEGRATED

617
00:22:28,760 --> 00:22:29,640
STRESS RESPONSE BECAUSE THERE

618
00:22:29,640 --> 00:22:30,960
ARE ACTUALLY FOUR DIFFERENT

619
00:22:30,960 --> 00:22:34,480
KINASES, EACH OF WHICH -- FOR

620
00:22:34,480 --> 00:22:39,040
INSTANCE, PERC AND EACH WILL

621
00:22:39,040 --> 00:22:42,120
PHOSPHORYLATE THE SAME RESIDUE

622
00:22:42,120 --> 00:22:44,400
LEADING TO THIS STEREOTYPED

623
00:22:44,400 --> 00:22:45,520
RESPONSE TO A VARIETY OF

624
00:22:45,520 --> 00:22:47,120
DIFFERENT CELLULAR STRESS.

625
00:22:47,120 --> 00:22:48,440
SO THIS HAD BEEN DEMONSTRATED

626
00:22:48,440 --> 00:22:50,600
VERY NICELY IN CULTURED CELLS

627
00:22:50,600 --> 00:22:52,360
BUT WE WONDERED CAN THIS

628
00:22:52,360 --> 00:22:54,360
ACTUALLY OCCUR IN VIVO IN A

629
00:22:54,360 --> 00:22:58,200
DISEASE RELEVANT MODEL SYSTEM.

630
00:22:58,200 --> 00:22:59,800
WE THOUGHT WE HAD A GOOD MODEL

631
00:22:59,800 --> 00:23:03,000
SYSTEM TO POTENTIALLY TEST THIS

632
00:23:03,000 --> 00:23:03,520
IDEA.

633
00:23:03,520 --> 00:23:05,280
SO WE FIRST ASKED IS THIS

634
00:23:05,280 --> 00:23:06,400
INTEGRATED STRESS RESPONSE

635
00:23:06,400 --> 00:23:07,800
ACTIVATED IN AFFECTED TISSUES OF

636
00:23:07,800 --> 00:23:08,880
OUR MOUSE MODEL.

637
00:23:08,880 --> 00:23:11,520
INDEED WE FOUND EIF2 ALPHA IS

638
00:23:11,520 --> 00:23:12,280
PHOSPHORYLATED BOTH IN THE HEART

639
00:23:12,280 --> 00:23:14,800
AND THE AFFECTED SKELETAL

640
00:23:14,800 --> 00:23:15,920
MUSCLE.

641
00:23:15,920 --> 00:23:18,080
WE NEXT ASKED IS THIS BEING

642
00:23:18,080 --> 00:23:19,840
SIGNALED BY OMA1 AND TO GET AT

643
00:23:19,840 --> 00:23:22,160
THIS QUESTION, WE KNOCKED DOWN

644
00:23:22,160 --> 00:23:24,840
OMA1 IN VIVO BY INJECTING THE

645
00:23:24,840 --> 00:23:26,760
ANIMALS AGAINST OMA1, WE

646
00:23:26,760 --> 00:23:27,880
ACHIEVED VERY GOOD KNOCK DOWN AT

647
00:23:27,880 --> 00:23:28,800
THE PROTEIN LEVEL IN THE HEART

648
00:23:28,800 --> 00:23:30,560
AND THIS SUPPRESSED THIS

649
00:23:30,560 --> 00:23:32,080
ACTIVATION OF THE INTEGRATED

650
00:23:32,080 --> 00:23:32,920
STRESS RESPONSE, INDICATING THAT

651
00:23:32,920 --> 00:23:35,400
IT IS BEING SIGNALED BY OMA1 IN

652
00:23:35,400 --> 00:23:36,040
VIVO.

653
00:23:36,040 --> 00:23:38,680
WE SAW VERY CONSISTENT RESPONSE

654
00:23:38,680 --> 00:23:43,480
IN THE TRANSCRIPTOMICS, WE SEE

655
00:23:43,480 --> 00:23:44,480
UPREGULATION IN THE -- HEARTS

656
00:23:44,480 --> 00:23:46,520
COMPARED TO THE WILD TYPE BUT

657
00:23:46,520 --> 00:23:47,840
TRANSCRIPTION FACTOR IS KNOWN TO

658
00:23:47,840 --> 00:23:50,800
BE PART OF -- AS WELL AS A

659
00:23:50,800 --> 00:23:59,400
NUMBER OF DOWNSTREAM TARGETS.

660
00:23:59,400 --> 00:24:01,080
IF WE LOOK AT MUTED HEARTS WE

661
00:24:01,080 --> 00:24:03,240
GET DOWN RG LAITION OF THE SAME

662
00:24:03,240 --> 00:24:03,800
TRANSCRIPTIONAL SIGNATURE

663
00:24:03,800 --> 00:24:06,320
INDICATING THAT.

664
00:24:06,320 --> 00:24:11,800
 OMA1 IS

665
00:24:11,800 --> 00:24:13,240
RESPONSIBLE IN MUTED HEARTS.

666
00:24:13,240 --> 00:24:15,080
WE NEXT ASKED IS THIS RESPONSE

667
00:24:15,080 --> 00:24:17,280
PROTECTIVE OR DETRIMENTAL TO

668
00:24:17,280 --> 00:24:20,560
THESE ANIMALS?

669
00:24:20,560 --> 00:24:24,600
WE CROSSED OUR CROSSED ANIMAL

670
00:24:24,600 --> 00:24:26,520
WITH -- WHAT WE FOUND IS IF THEY

671
00:24:26,520 --> 00:24:27,560
CAN'T TURN ON THE STRESS

672
00:24:27,560 --> 00:24:28,840
RESPONSE MOST OF THE MICE WILL

673
00:24:28,840 --> 00:24:30,160
DIE IN THE FIRST EIGHT DAYS OF

674
00:24:30,160 --> 00:24:30,960
LIFE.

675
00:24:30,960 --> 00:24:32,560
ABOUT A THIRD OF THEM CAN

676
00:24:32,560 --> 00:24:36,080
SURVIVE LONGER, TO ABOUT 14 OR

677
00:24:36,080 --> 00:24:37,280
15 WEEKS, BUT THOSE ANIMALS HAVE

678
00:24:37,280 --> 00:24:38,840
THESE MASSIVELY ENLARGED HEARTS.

679
00:24:38,840 --> 00:24:40,920
SO WE THINK THAT THIS STRESS

680
00:24:40,920 --> 00:24:42,240
RESPONSE IS HELPING THE CELL AND

681
00:24:42,240 --> 00:24:45,360
THE TISSUE COPE WITH THE

682
00:24:45,360 --> 00:24:45,960
MITOCHONDRIAL DAMAGE THAT'S

683
00:24:45,960 --> 00:24:48,040
BEING CAUSED BY THIS PROTEIN

684
00:24:48,040 --> 00:24:49,680
MISFOLDING WITHIN THE

685
00:24:49,680 --> 00:24:50,400
MITOCHONDRIAL CRISTAE.

686
00:24:50,400 --> 00:24:52,480
SO TO PUT THIS TOGETHER, WE HAVE

687
00:24:52,480 --> 00:24:54,120
THIS PROTEIN MISFOLDING WITHIN

688
00:24:54,120 --> 00:24:56,400
THE MITOCHONDRIAL -- AND IT'S

689
00:24:56,400 --> 00:24:57,760
ACTIVATING THIS TRANSCRIPTIONAL

690
00:24:57,760 --> 00:25:00,520
RESPONSE THAT LEADS TO A NUMBER

691
00:25:00,520 --> 00:25:01,920
OF METABOLIC CHANGES INCLUDING

692
00:25:01,920 --> 00:25:03,560
UPREGULATION OF PATHWAYS

693
00:25:03,560 --> 00:25:05,400
INVOLVED IN -- SYNTHESIS AND

694
00:25:05,400 --> 00:25:06,480
CARBON METABOLISM AND IS BEING

695
00:25:06,480 --> 00:25:09,120
SIGNALED BY OMA1 AND DELE1.

696
00:25:09,120 --> 00:25:11,480
THIS RAISES THE QUESTION, IS

697
00:25:11,480 --> 00:25:12,520
THIS A VERY GENERAL RESPONSE, IS

698
00:25:12,520 --> 00:25:14,600
IT ALSO SIGNALING OTHER FORMS OF

699
00:25:14,600 --> 00:25:15,880
MITOCHONDRIAL STRESS IN THE

700
00:25:15,880 --> 00:25:18,520
HEART AND OTHER ORGANS.

701
00:25:18,520 --> 00:25:20,360
AND A COUPLE OF PAPERS THAT HAVE

702
00:25:20,360 --> 00:25:22,680
BEEN PUBLISHED SINCE WE

703
00:25:22,680 --> 00:25:24,080
PUBLISHED THIS FINDING SUGGESTS

704
00:25:24,080 --> 00:25:25,440
THIS IS PROBABLY A MAJOR

705
00:25:25,440 --> 00:25:27,280
RESPONSE TO DIFFERENT FORMS OF

706
00:25:27,280 --> 00:25:27,720
MITOCHONDRIAL STRESS.

707
00:25:27,720 --> 00:25:30,320
THERE WAS A PAPER WHICH

708
00:25:30,320 --> 00:25:34,160
DEMONSTRATED THAT IF YOU INHIBIT

709
00:25:34,160 --> 00:25:35,240
CARDIO -- THERE IS IMPORTANT FOR

710
00:25:35,240 --> 00:25:36,560
THE INNER MEMBRANE OF

711
00:25:36,560 --> 00:25:37,760
MITOCHONDRIA WITH KNOCKOUTS OF

712
00:25:37,760 --> 00:25:39,200
EITHER OF THESE TWO PROTEINS YOU

713
00:25:39,200 --> 00:25:40,880
GET VERY SIMILAR TRANSCRIPTIONAL

714
00:25:40,880 --> 00:25:41,200
RESPONSE.

715
00:25:41,200 --> 00:25:44,680
THIS IS DEPENDENT ON THE -- AS

716
00:25:44,680 --> 00:25:48,840
WELL AS PHOSPHORYLATION AND VERY

717
00:25:48,840 --> 00:25:50,680
RECENTLY IT WAS DEMONSTRATED IF

718
00:25:50,680 --> 00:25:51,880
YOU CREATE DEFICIENCY IN THE

719
00:25:51,880 --> 00:25:54,400
HEART BY KNOCKING OUT THE

720
00:25:54,400 --> 00:25:57,680
SUBUNIT OF THE OXPHOS CHAIN ON

721
00:25:57,680 --> 00:26:00,400
COX10, YOU GET A VERY SIMILAR

722
00:26:00,400 --> 00:26:01,400
TRANSCRIPTIONAL RESPONSE,

723
00:26:01,400 --> 00:26:05,440
SIMILARLY DEPENDENT ON DELE SO

724
00:26:05,440 --> 00:26:06,520
WE THINK THIS IS GOING TO TURN

725
00:26:06,520 --> 00:26:12,360
OUT TO BE PREDOMINANTLY -- IN

726
00:26:12,360 --> 00:26:13,000
VIVO ORGANISMS.

727
00:26:13,000 --> 00:26:14,880
SO TO SUMMARIZE OUR FINDINGS, WE

728
00:26:14,880 --> 00:26:17,480
HAVE MUTATIONS IN C2 AND C10

729
00:26:17,480 --> 00:26:19,040
THAT CAUSE NEUROTEE GENERATIVE

730
00:26:19,040 --> 00:26:21,320
DISORDERS WITH A CLEAR

731
00:26:21,320 --> 00:26:22,320
GENOTYPE-PHENOTYPE RELATION SHI.

732
00:26:22,320 --> 00:26:24,400
DOMINANT MUTATIONS IN C2 AND C10

733
00:26:24,400 --> 00:26:29,080
CAUSES PROTEINS TO MISFOLD AND

734
00:26:29,080 --> 00:26:35,440
LICELY -- THE CHCHD2 -- LEADS TO

735
00:26:35,440 --> 00:26:39,280
MITOCHONDRIAL MYOPATHIES AND

736
00:26:39,280 --> 00:26:41,120
STRESS RESPONSE WITH LOCAL AND

737
00:26:41,120 --> 00:26:44,840
GLOBAL RESPONSES THAT PROTECT

738
00:26:44,840 --> 00:26:45,840
FROM MITOCHONDRIAL DAMAGE.

739
00:26:45,840 --> 00:26:56,400
I JUST WANT TO ACKNOWLEDGE A --

740
00:26:57,680 --> 00:26:59,160
BIOLOGIST AND LAB MANAGER WITHIN

741
00:26:59,160 --> 00:26:59,600
THE LAB.

742
00:26:59,600 --> 00:27:01,480
AND WITH THAT, I'LL TURN IT OVER

743
00:27:01,480 --> 00:27:03,440
NOW TO CLAIRE, WHO WILL TELL BUT

744
00:27:03,440 --> 00:27:07,680
A DIFFERENT STRESS RESPONSE.

745
00:27:07,680 --> 00:27:10,720
>>THANKS, DEREK, AND
THANK YOU,

746
00:27:10,720 --> 00:27:13,800
TOM, FOR THE NICE INTRODUCTION.

747
00:27:13,800 --> 00:27:15,880
SO TODAY I'M GOING TO TELL YOU

748
00:27:15,880 --> 00:27:17,720
ABOUT SOME OTHER TYPES --

749
00:27:17,720 --> 00:27:21,800
ADDITIONAL TYPES OF STRESS

750
00:27:21,800 --> 00:27:22,560
RESPONSES THAT WE THINK ARE

751
00:27:22,560 --> 00:27:24,320
IMPORTANT IN THE CONTEXT OF

752
00:27:24,320 --> 00:27:26,600
NEURODEGENERATION.

753
00:27:26,600 --> 00:27:28,680
AND THOSE ARE AXON INJURY

754
00:27:28,680 --> 00:27:29,000
RESPONSES.

755
00:27:29,000 --> 00:27:31,760
AND SO IN MY LAB, IN NICHD,

756
00:27:31,760 --> 00:27:34,480
WE'RE REALLY INTERESTED IN HOW

757
00:27:34,480 --> 00:27:36,000
NEURONS RESPOND TO INJURY BY

758
00:27:36,000 --> 00:27:39,080
SPECIFIC STRESS RESPONSES IN

759
00:27:39,080 --> 00:27:40,160
PARTICULAR, AXON INJURY

760
00:27:40,160 --> 00:27:40,440
RESPONSES.

761
00:27:40,440 --> 00:27:42,240
I DO THINK THIS WORK WILL HELP

762
00:27:42,240 --> 00:27:44,120
US BETTER UNDERSTAND THE

763
00:27:44,120 --> 00:27:46,080
PATHOPHYSIOLOGY OF

764
00:27:46,080 --> 00:27:46,960
NEURODEGENERATIVE DISEASE, SO

765
00:27:46,960 --> 00:27:48,480
TODAY I'M GOING TO SHOW YOU A

766
00:27:48,480 --> 00:27:50,120
BRIEF INTRODUCTION ON ONE OF THE

767
00:27:50,120 --> 00:27:52,080
PATHWAYS THAT WE FOCUS ON, AND

768
00:27:52,080 --> 00:27:54,320
THEN SHARE WITH YOU THREE

769
00:27:54,320 --> 00:27:55,800
VIGNETTES OF WORK THAT WE HAVE

770
00:27:55,800 --> 00:27:58,320
DONE IN MY LAB TO KIND OF

771
00:27:58,320 --> 00:28:00,880
ILLUSTRATE THIS IDEA.

772
00:28:00,880 --> 00:28:04,040
JUST TO SHOW THAT I HAVE NO

773
00:28:04,040 --> 00:28:05,320
DISCLOSURES, AND TODAY IF THERE

774
00:28:05,320 --> 00:28:08,280
IS A LEARNING OBJECTIVE, I'D

775
00:28:08,280 --> 00:28:10,960
LIKE TO CONVINCE YOU THAT AXON

776
00:28:10,960 --> 00:28:12,880
DAMAGE SIGNALING IS A TYPE OF

777
00:28:12,880 --> 00:28:14,960
NEURONAL STRESS THAT'S RELEVANT

778
00:28:14,960 --> 00:28:18,800
TO MANY CONDITIONS THAT INVOLVE

779
00:28:18,800 --> 00:28:21,520
NEURODEGENERATION, INCLUDING

780
00:28:21,520 --> 00:28:24,160
SEVERAL DISEASES, STROKE,

781
00:28:24,160 --> 00:28:25,040
TRAUMATIC INJURIES TO THE BRAIN

782
00:28:25,040 --> 00:28:27,120
AS WELL.

783
00:28:27,120 --> 00:28:29,200
AND IN MY LAB, WE USE DIFFERENT

784
00:28:29,200 --> 00:28:32,360
TYPES OF MODELS, INCLUDING THE

785
00:28:32,360 --> 00:28:33,800
TYPES OF PRECISION MOUSE MODELS

786
00:28:33,800 --> 00:28:35,440
OF DISEASE THAT YOU HEARD FROM

787
00:28:35,440 --> 00:28:35,760
DEREK.

788
00:28:35,760 --> 00:28:36,880
I'M NOT GOING TO TALK ABOUT

789
00:28:36,880 --> 00:28:39,720
THOSE TODAY.

790
00:28:39,720 --> 00:28:42,840
WE ALSO HAVE MOUSE MODELS OF

791
00:28:42,840 --> 00:28:45,160
TRAUMATIC NERVE INJURY AND BRAIN

792
00:28:45,160 --> 00:28:48,800
INJURY, AND WE TRY TO LEVERAGE

793
00:28:48,800 --> 00:28:50,720
SINGLE CELL SEQUENCING

794
00:28:50,720 --> 00:28:53,240
TECHNOLOGY TO STUDY DIFFERENTIAL

795
00:28:53,240 --> 00:28:54,800
AND CELL TYPE-SPECIFIC RESPONSES

796
00:28:54,800 --> 00:28:58,480
TO INJURY AND DISEASE, AS WELL

797
00:28:58,480 --> 00:29:04,200
AS WE HAVE STARTED USING HUMAN

798
00:29:04,200 --> 00:29:06,160
IPSC-DERIVED NEURONS TO

799
00:29:06,160 --> 00:29:08,560
TRANSLATE AND HAVE A TRACTABLE

800
00:29:08,560 --> 00:29:09,760
SYSTEM FOR CELL BIOLOGICAL

801
00:29:09,760 --> 00:29:10,200
STUDIES.

802
00:29:10,200 --> 00:29:11,400
OKAY.

803
00:29:11,400 --> 00:29:13,880
SO IN VERY SIMPLE TERMS,

804
00:29:13,880 --> 00:29:15,120
NEURODEGENERATION CAN BE CAUSED

805
00:29:15,120 --> 00:29:17,880
BY A COMBINATION OF GENETIC

806
00:29:17,880 --> 00:29:18,760
PREDISPOSITION AS WELL AS

807
00:29:18,760 --> 00:29:19,960
ENVIRONMENTAL FACTORS

808
00:29:19,960 --> 00:29:23,320
EXPERIENCED DURING DEVELOPMENT

809
00:29:23,320 --> 00:29:24,120
AND IN THE LIFESPAN.

810
00:29:24,120 --> 00:29:26,840
IN MY LAB, WE'RE PARTICULARLY

811
00:29:26,840 --> 00:29:28,040
INTERESTED IN THE COMMON

812
00:29:28,040 --> 00:29:32,200
DOWNSTREAM PATHWAYS THAT LEAD TO

813
00:29:32,200 --> 00:29:33,600
NEURODEGENERATION.

814
00:29:33,600 --> 00:29:36,120
IN PARTICULAR, ONE OF THE

815
00:29:36,120 --> 00:29:37,680
PATHWAYS THAT WE FOCUSED ON

816
00:29:37,680 --> 00:29:39,880
QUITE A LOT SINCE I STARTED

817
00:29:39,880 --> 00:29:44,760
WORKING ON THIS WHEN I WAS AT

818
00:29:44,760 --> 00:29:50,160
GENENTECH IS DLK, AND MAPP.

819
00:29:50,160 --> 00:29:59,000
MAP3K12.THE IDEA IS IF WE CAN TT

820
00:29:59,000 --> 00:29:59,960
PATHWAYS LIKE THIS THAT ARE

821
00:29:59,960 --> 00:30:01,160
RELATIVELY I WOULD SAY A

822
00:30:01,160 --> 00:30:02,680
DOWNSTREAM PROCESS IN THE

823
00:30:02,680 --> 00:30:06,360
CONTEXT OF, YOU KNOW, THE STEPS

824
00:30:06,360 --> 00:30:10,880
LEADING TOWARDS LOSS OF NEURONS,

825
00:30:10,880 --> 00:30:12,320
THEN THIS COULD BE A POTENTIALLY

826
00:30:12,320 --> 00:30:17,000
VALUABLE WAY TO PREVENT NEURONAL

827
00:30:17,000 --> 00:30:18,080
CELL DEATH IN THE CONTEXT OF

828
00:30:18,080 --> 00:30:24,120
MANY DIFFERENT DISEASES.

829
00:30:24,120 --> 00:30:26,400
SO HOW WE CAME TO STUDY THIS WAS

830
00:30:26,400 --> 00:30:28,240
ACTUALLY THANKS TO THE FINDINGS

831
00:30:28,240 --> 00:30:30,040
THAT MY COLLEAGUES HAD MADE AT

832
00:30:30,040 --> 00:30:32,640
GENENTECH, WHICH IS THAT DLK IS

833
00:30:32,640 --> 00:30:34,840
ACTUALLY REALLY IMPORTANT IN

834
00:30:34,840 --> 00:30:36,800
DRIVING A PARTICULAR KIND OF

835
00:30:36,800 --> 00:30:38,680
NEURONAL CELL DEATH THAT HAPPENS

836
00:30:38,680 --> 00:30:40,400
DURING DEVELOPMENT, WHICH IS A

837
00:30:40,400 --> 00:30:42,360
NORMAL AND HEALTHY PROCESS.

838
00:30:42,360 --> 00:30:45,880
SO HERE I'M SHOW YOU ING YOU AN

839
00:30:45,880 --> 00:30:46,520
EXAMPLE.

840
00:30:46,520 --> 00:30:48,720
THESE ARE -- THE GREEN CELLS,

841
00:30:48,720 --> 00:30:55,400
THE GREEN CELLS ARE MOTOR NEURON

842
00:30:55,400 --> 00:30:56,400
NUCLEI FROM THE SPINAL CORD OF A

843
00:30:56,400 --> 00:30:57,440
DEVELOPING MOUSE, AND YOU CAN

844
00:30:57,440 --> 00:30:59,760
SEE THAT THERE ARE MANY MORE OF

845
00:30:59,760 --> 00:31:10,160
THEM, EMBRYONIC DATA --

846
00:31:11,520 --> 00:31:12,520
BASICALLY DLK IS RESPONSIBLE FOR

847
00:31:12,520 --> 00:31:14,200
A WAVE OF NEURONAL CELL DEATH

848
00:31:14,200 --> 00:31:16,280
THAT OCCURS DURING DEVELOPMENT

849
00:31:16,280 --> 00:31:19,560
AS SHOWN HERE IN A KNOCKOUT

850
00:31:19,560 --> 00:31:21,560
ANIMAL, THIS FAILS TO OCCUR.

851
00:31:21,560 --> 00:31:25,080
AND SO THE VERY SIMPLE QUESTION

852
00:31:25,080 --> 00:31:27,200
WE ASKED WAS, WELL, IF THIS

853
00:31:27,200 --> 00:31:27,880
HAPPENS DURING NORMAL

854
00:31:27,880 --> 00:31:29,640
DEVELOPMENT AND DLK SIGNALS THE

855
00:31:29,640 --> 00:31:33,040
CELLS TO DIE, COULD THIS PATHWAY

856
00:31:33,040 --> 00:31:34,440
POTENTIALLY BE ACTIVATED AGAIN

857
00:31:34,440 --> 00:31:39,240
IN THE CONTEXT OF DISEASE IN A

858
00:31:39,240 --> 00:31:40,240
MATURE ORGANISM?

859
00:31:40,240 --> 00:31:44,920
SO TO DO THIS, I CROSSED A MOUSE

860
00:31:44,920 --> 00:31:47,120
MODEL OF, IN THIS CASE, ALS, SO

861
00:31:47,120 --> 00:31:48,920
IT'S A MOUSE THAT OVEREXPRESSES

862
00:31:48,920 --> 00:31:52,520
A MUTANT VERSION OF THE GENE

863
00:31:52,520 --> 00:31:55,360
THAT CAUSES EARLY ONSET ALS.

864
00:31:55,360 --> 00:31:56,880
AND SO YOU CAN SEE THAT IN

865
00:31:56,880 --> 00:31:58,320
THIS -- THE MOUSE MODEL FOR THIS

866
00:31:58,320 --> 00:31:59,840
DISEASE, THE MOTOR NEURONS THAT

867
00:31:59,840 --> 00:32:06,200
ARE LABELS BY THIS TRANS IF HE

868
00:32:06,200 --> 00:32:07,400
RACE STAIN ARE LOST.

869
00:32:07,400 --> 00:32:11,000
I CROSSED THESE MICE TO

870
00:32:11,000 --> 00:32:12,760
INDUCIBLE KNOCKOUTS OF DLK, SO

871
00:32:12,760 --> 00:32:16,280
THAT WE COULD BLOCK DLK

872
00:32:16,280 --> 00:32:17,560
SIGNALING IN THE MATURE

873
00:32:17,560 --> 00:32:17,880
ORGANISM.

874
00:32:17,880 --> 00:32:19,080
AND YOU CAN SEE HERE THAT THIS

875
00:32:19,080 --> 00:32:24,120
WAS ACTUALLY QUITE POWERFUL IN

876
00:32:24,120 --> 00:32:25,240
TERMS OF PREVENTING THESE CELLS

877
00:32:25,240 --> 00:32:30,480
FROM DYING.

878
00:32:30,480 --> 00:32:33,360
SO A LOT OF BASIC RESEARCH HAS

879
00:32:33,360 --> 00:32:34,560
UNCOVERED REALLY INTERESTING

880
00:32:34,560 --> 00:32:35,800
ASPECTS OF DLK SIGNALING, AND

881
00:32:35,800 --> 00:32:37,200
I'M GOING TO TRY TO SUMMARIZE

882
00:32:37,200 --> 00:32:39,600
THOSE IN THE FOLLOWING SLIDES.

883
00:32:39,600 --> 00:32:42,240
AND IT TURNS OUT THAT IN THE

884
00:32:42,240 --> 00:32:44,480
COURSE EVER THESE STUDIES, ONE

885
00:32:44,480 --> 00:32:46,040
OF THE BEST WAYS TO ACTIVATE DLK

886
00:32:46,040 --> 00:32:47,680
IS ACTUALLY BY INJURING THE

887
00:32:47,680 --> 00:32:48,520
AXON.

888
00:32:48,520 --> 00:32:49,760
SO IF YOU CAUSE AXON DAMAGE, YOU

889
00:32:49,760 --> 00:32:53,280
CAN TU TURN THE PATHWAY ON.

890
00:32:53,280 --> 00:33:00,480
WE LIKE TO USE THIS, THERE'S A L

891
00:33:00,480 --> 00:33:01,960
TO STUDY THE MODEL AND TO DRIVE

892
00:33:01,960 --> 00:33:02,120
IT.

893
00:33:02,120 --> 00:33:03,480
SO HERE'S THE SUMMARY.

894
00:33:03,480 --> 00:33:05,560
AXON DAMAGE CAN CAUSE THE

895
00:33:05,560 --> 00:33:07,160
ACTIVATION OF DLK, WHICH AS I

896
00:33:07,160 --> 00:33:10,480
MENTIONED EARLIER IS A MAP

897
00:33:10,480 --> 00:33:13,760
TRIPLE KINASE, RESPONSIBLE FOR

898
00:33:13,760 --> 00:33:15,400
PHOSPHORYLATING DOWNSTREAM

899
00:33:15,400 --> 00:33:16,720
SUBSTRATES.

900
00:33:16,720 --> 00:33:18,800
AND WHEN I SAY AXON INJURY, AND

901
00:33:18,800 --> 00:33:21,200
HERE'S KIND OF THE RELEVANCE TO

902
00:33:21,200 --> 00:33:23,800
NEURODEGENERATION THAT I HOPE TO

903
00:33:23,800 --> 00:33:25,240
GET ACROSS TODAY, IT'S NOT

904
00:33:25,240 --> 00:33:29,160
SIMPLY MECHANICAL INJURY OF AN

905
00:33:29,160 --> 00:33:31,360
AXON, BUT I MEAN THIS IN A VERY

906
00:33:31,360 --> 00:33:32,880
WIDE SENSE, SO WE CAN HAVE

907
00:33:32,880 --> 00:33:33,960
MECHANICAL INJURY, YOU COULD

908
00:33:33,960 --> 00:33:36,280
HAVE THE TYPES OF STRESSES THAT

909
00:33:36,280 --> 00:33:37,280
DEREK WAS TALKING ABOUT THAT

910
00:33:37,280 --> 00:33:40,680
MIGHT BE UPSTREAM OF THIS AXON

911
00:33:40,680 --> 00:33:43,600
TRANSPORT DISRUPTION AND

912
00:33:43,600 --> 00:33:44,600
PROTEOTOXIC STRESS.

913
00:33:44,600 --> 00:33:46,120
BECAUSE FOR EXAMPLE, IN A MOUSE

914
00:33:46,120 --> 00:33:47,760
MODEL OF ALS THAT I SHOWED YOU,

915
00:33:47,760 --> 00:33:49,960
THOSE ANIMALS ARE NOT UNDERGOING

916
00:33:49,960 --> 00:33:51,280
MECHANICAL INJURY, BUT SOME

917
00:33:51,280 --> 00:33:56,560
OTHER TRIGGER.

918
00:33:56,560 --> 00:33:59,040
SO THIS KINASE PHOSPHORYLATION

919
00:33:59,040 --> 00:34:01,600
SETS OFF THIS RETROGRADE SIGNAL

920
00:34:01,600 --> 00:34:04,320
THAT CAN RESULT IN A

921
00:34:04,320 --> 00:34:05,520
TRANSCRIPTIONAL RESPONSE SO WE

922
00:34:05,520 --> 00:34:06,520
HAVE AN UPREGULATION OF

923
00:34:06,520 --> 00:34:07,840
TRANSCRIPTION FACTORS AND THE

924
00:34:07,840 --> 00:34:11,160
ACTIVE FORM OF THIS

925
00:34:11,160 --> 00:34:12,920
TRANSCRIPTION FACTOR WHICH IS A

926
00:34:12,920 --> 00:34:13,760
PHOSPHORYLATED VERSION DIRECTLY

927
00:34:13,760 --> 00:34:16,280
DOWNSTREAM OF THIS CASCADE OF

928
00:34:16,280 --> 00:34:18,600
THIS KINASE CASCADE.

929
00:34:18,600 --> 00:34:20,880
NOW, THAT'S THE PART OF THE CELL

930
00:34:20,880 --> 00:34:22,400
THAT'S CONNECTED TO THE CELL

931
00:34:22,400 --> 00:34:22,720
BODY.

932
00:34:22,720 --> 00:34:25,960
AT THE OTHER END, WHAT WE CALL

933
00:34:25,960 --> 00:34:28,000
THE DISTAL AXON, THIS PART OF

934
00:34:28,000 --> 00:34:31,760
THE AXON UNDERGOES AXON

935
00:34:31,760 --> 00:34:33,840
DEGENERATION, AND THIS INVOLVES

936
00:34:33,840 --> 00:34:35,000
OTHER GENES THAT I'M NOT GOING

937
00:34:35,000 --> 00:34:37,880
TO DESCRIBE TODAY FOR THE SAKE

938
00:34:37,880 --> 00:34:39,600
OF TIME, BUT ONLY TO SAY THAT

939
00:34:39,600 --> 00:34:41,440
DLK ALSO CONTRIBUTES TO THIS

940
00:34:41,440 --> 00:34:45,400
TYPE OF WHAT'S KNOWN AT

941
00:34:45,400 --> 00:34:46,280
WALLERIAN DEGENERATION.

942
00:34:46,280 --> 00:34:48,600
IN ADDITION TO WHAT I'VE JUST

943
00:34:48,600 --> 00:34:51,080
DESCRIBED IN TERMS OF AXON

944
00:34:51,080 --> 00:34:53,600
DEGENERATION AND ACTIVATION OF A

945
00:34:53,600 --> 00:34:55,480
TRANSCRIPTIONAL RESPONSE, THIS

946
00:34:55,480 --> 00:34:56,680
RESPONSE CAN ACTUALLY LEAD TO

947
00:34:56,680 --> 00:34:58,440
MANY DIFFERENT OUTCOMES,

948
00:34:58,440 --> 00:35:00,640
INCLUDING THINGS LIKE THE NEURON

949
00:35:00,640 --> 00:35:02,080
CELL DEATH THAT I DESCRIBED

950
00:35:02,080 --> 00:35:04,600
EARLIER BUT ALSO IN SOME CASES

951
00:35:04,600 --> 00:35:07,240
TO REPAIR AND REGENERATION.

952
00:35:07,240 --> 00:35:12,360
AND THIS IS MOST NOTABLY BEEN

953
00:35:12,360 --> 00:35:14,560
SHOWN IN WORMS, IN FLIES AND IN

954
00:35:14,560 --> 00:35:16,880
MICE FOR PERIPHERAL NEURONS.

955
00:35:16,880 --> 00:35:20,360
OKAY.

956
00:35:20,360 --> 00:35:21,600
SO ONE THING MY LAB DEMONSTRATED

957
00:35:21,600 --> 00:35:22,680
WAS ACTUALLY THAT IN ADDITION TO

958
00:35:22,680 --> 00:35:24,400
ALL OF THESE THINGS THAT I

959
00:35:24,400 --> 00:35:26,080
DESCRIBED WHICH ARE REALLY

960
00:35:26,080 --> 00:35:27,400
INTRINSIC TO THE INJURED NEURON,

961
00:35:27,400 --> 00:35:29,360
THIS PATHWAY CAN ALSO SIGNAL TO

962
00:35:29,360 --> 00:35:31,640
THE OUTSIDE OF THE INJURED CELL,

963
00:35:31,640 --> 00:35:35,800
AND IN THIS CASE, THE VIGNETTE

964
00:35:35,800 --> 00:35:36,880
I'M GOING TO SHARE WITH YOU NOW

965
00:35:36,880 --> 00:35:40,640
IS THAT ONE OF THE

966
00:35:40,640 --> 00:35:41,320
TRANSCRIPTIONAL RESPONSES

967
00:35:41,320 --> 00:35:42,840
ACTUALLY CAN DRIVE

968
00:35:42,840 --> 00:35:43,240
NEUROINFLAMMATION.

969
00:35:43,240 --> 00:35:46,240
SO THIS WORK WAS DONE BY THIS

970
00:35:46,240 --> 00:35:50,320
TEAM IN MY LAB, AND WE PUBLISHED

971
00:35:50,320 --> 00:35:54,880
THIS JUST AS A KIND OF -- TO

972
00:35:54,880 --> 00:35:56,080
SITUATE YOU IN TERMS OF THE

973
00:35:56,080 --> 00:35:57,080
ANATOMY I'M GOING TO BE

974
00:35:57,080 --> 00:35:57,400
DESCRIBING.

975
00:35:57,400 --> 00:35:59,520
SO I'M GOING TO BE TALKING ABOUT

976
00:35:59,520 --> 00:36:01,040
THE SENSORY NEURONS THAT RESIDE

977
00:36:01,040 --> 00:36:03,120
IN THE DORSAL ROOT GANGLIA THAT

978
00:36:03,120 --> 00:36:06,280
LINE THE SPINAL CORD.

979
00:36:06,280 --> 00:36:08,160
AND I'M ALSO -- SO THESE ARE THE

980
00:36:08,160 --> 00:36:14,200
DRG NEURONS, AND THEIR CELL BODY

981
00:36:14,200 --> 00:36:15,840
PROJECTS AN AXON WHICH

982
00:36:15,840 --> 00:36:17,240
BIFURCATES AND ACTUALLY PROJECTS

983
00:36:17,240 --> 00:36:18,720
TO, ON THE ONE HAND, THE DORSAL

984
00:36:18,720 --> 00:36:20,200
HORN OF THE SPINAL CORD.

985
00:36:20,200 --> 00:36:22,520
AND AT THE OTHER END, TO THE

986
00:36:22,520 --> 00:36:26,240
PERIPHERY.

987
00:36:26,240 --> 00:36:28,200
AND THEN WHEN WE DO THE TYPE OF

988
00:36:28,200 --> 00:36:29,880
NERVE INJURY THAT I'M ABOUT TO

989
00:36:29,880 --> 00:36:32,880
DESCRIBE, WHICH WOULD BE, FOR

990
00:36:32,880 --> 00:36:35,560
EXAMPLE, CRUSHING OR CUTTING THE

991
00:36:35,560 --> 00:36:38,200
SCIATIC NERVE, WE'RE ALSO

992
00:36:38,200 --> 00:36:40,040
INJURING THE SPINAL MOTOR

993
00:36:40,040 --> 00:36:41,480
NEURONS AND THESE PROJECT THEIR

994
00:36:41,480 --> 00:36:44,560
AXON TO THE PERIPHERAL MUSCLE TO

995
00:36:44,560 --> 00:36:47,640
GENERATE MUSCLE CONTRACTION.

996
00:36:47,640 --> 00:36:50,040
SO WHAT I'M SHOWING YOU HERE IS

997
00:36:50,040 --> 00:36:53,720
ACTUALLY A MOUSE SPINAL CORD.

998
00:36:53,720 --> 00:36:55,920
THIS IS FROM AN ANIMAL WHICH HAS

999
00:36:55,920 --> 00:36:57,280
RECEIVED THIS TYPE OF SCIATIC

1000
00:36:57,280 --> 00:37:00,000
NERVE INJURY ON THIS SIDE ONLY,

1001
00:37:00,000 --> 00:37:02,760
AND WE HAVE STAINED THE WHOLE

1002
00:37:02,760 --> 00:37:05,040
TISSUE TO REVEAL THE MICROGLIA

1003
00:37:05,040 --> 00:37:05,480
IN THE SPINAL CORD.

1004
00:37:05,480 --> 00:37:07,600
AND YOU CAN APPRECIATE THAT WE

1005
00:37:07,600 --> 00:37:09,320
HAVE TWO CLOUDS OF MICROGLIA.

1006
00:37:09,320 --> 00:37:11,200
ONE OF THEM IN THE DORSAL HORN

1007
00:37:11,200 --> 00:37:12,480
WHICH IS WHERE THE SENSORY

1008
00:37:12,480 --> 00:37:13,720
NEURONS THAT WE INJURED PROJECT

1009
00:37:13,720 --> 00:37:15,680
TO, AND ANOTHER ONE IN THE

1010
00:37:15,680 --> 00:37:17,560
VENTRAL HORN, HERE, WHICH IS

1011
00:37:17,560 --> 00:37:18,760
WHERE -- WHICH IS SURROUNDING

1012
00:37:18,760 --> 00:37:22,680
THE MOTOR NEURON CELL BODIES OF

1013
00:37:22,680 --> 00:37:23,920
THE CELLS -- OF THE MOTOR

1014
00:37:23,920 --> 00:37:28,080
NEURONS THAT WE INJURED.

1015
00:37:28,080 --> 00:37:29,960
AND SO WE LOOKED TO SEE, AND

1016
00:37:29,960 --> 00:37:31,360
HERE I'M SHOWING YOU BY THE TOP

1017
00:37:31,360 --> 00:37:33,000
VIEW WHAT THIS WOULD LOOK LIKE

1018
00:37:33,000 --> 00:37:36,280
IN AN ANIMAL THAT LACKED DLK.

1019
00:37:36,280 --> 00:37:39,920
SO TO MODEL BLOCKING DLK.

1020
00:37:39,920 --> 00:37:42,120
AND WHAT WE OBSERVED IS THAT

1021
00:37:42,120 --> 00:37:46,040
THIS NEUROINFLAMMATORY RESPONSE

1022
00:37:46,040 --> 00:37:48,560
WAS COMPLETELY PREVENTED, AND SO

1023
00:37:48,560 --> 00:37:49,680
JUST QUITE RAPIDLY, I JUST WANT

1024
00:37:49,680 --> 00:37:51,760
TO SHOW YOU EVIDENCE HERE THAT

1025
00:37:51,760 --> 00:37:53,960
WHAT WE UNDERSTAND NOW, HOW THIS

1026
00:37:53,960 --> 00:37:57,760
WORKS, IS THAT DLK DRIVES

1027
00:37:57,760 --> 00:38:00,520
UPREGULATION OF THIS GENE CALLED

1028
00:38:00,520 --> 00:38:02,320
CSF 1, WHICH IS ACTUALLY A

1029
00:38:02,320 --> 00:38:03,360
CYTOKINE THAT'S NOT NORMALLY

1030
00:38:03,360 --> 00:38:04,600
EXPRESSED IN NEURONS, AND YOU

1031
00:38:04,600 --> 00:38:06,560
CAN SEE THAT THE UPREGULATION OF

1032
00:38:06,560 --> 00:38:08,360
THIS GENE FAILS TO OCCUR IN THE

1033
00:38:08,360 --> 00:38:13,280
DR DP.s,  RGs, FOR EXAMPLE, OF K

1034
00:38:13,280 --> 00:38:14,400
KNOCKOUT, SO WHAT WE THINK

1035
00:38:14,400 --> 00:38:18,240
HAPPENS IS THAT UPON INJURY, THE

1036
00:38:18,240 --> 00:38:22,280
DLK PATHWAY IS ACTIVATED, IT

1037
00:38:22,280 --> 00:38:24,320
UPREGULATES CSF 1 IN THE SENSORY

1038
00:38:24,320 --> 00:38:27,120
NEURONS AND THE MOTOR NEURONS.

1039
00:38:27,120 --> 00:38:27,800
 BY

1040
00:38:27,800 --> 00:38:29,320
THIS RETROGRADE SIGNAL THAT I

1041
00:38:29,320 --> 00:38:31,120
DESCRIBED EARLIER, AND THEN THE

1042
00:38:31,120 --> 00:38:33,720
UPREGULATION OF CSF 1 AND THOSE

1043
00:38:33,720 --> 00:38:35,080
NEURONS CAUSES LOCAL

1044
00:38:35,080 --> 00:38:36,800
PROLIFERATION AND ACTIVATION OF

1045
00:38:36,800 --> 00:38:38,880
THE MICROGLIA, WHICH EXPRESS THE

1046
00:38:38,880 --> 00:38:40,160
RECEPTOR FOR THIS CYTOKINE.

1047
00:38:40,160 --> 00:38:41,280
AND THAT'S WHY WE HAVE TWO

1048
00:38:41,280 --> 00:38:43,080
CLOUDS OF MICROGLIA, HERE AND

1049
00:38:43,080 --> 00:38:46,240
HERE.

1050
00:38:46,240 --> 00:38:48,160
NOW, I'VE SHARED WITH YOU HOW

1051
00:38:48,160 --> 00:38:49,440
DLK STRESS SIGNALING CAN

1052
00:38:49,440 --> 00:38:52,000
UPREGULATE A GENE LIKE CSF 1 AND

1053
00:38:52,000 --> 00:38:53,520
INVOLVE GLIAL CELLS IN A

1054
00:38:53,520 --> 00:38:54,720
TISSUE-WIDE STRESS RESPONSE.

1055
00:38:54,720 --> 00:38:56,280
AND WHAT WE REALLY WANTED TO

1056
00:38:56,280 --> 00:38:58,000
FIGURE OUT WAS A WAY IN WHICH WE

1057
00:38:58,000 --> 00:38:59,680
COULD KNOW THE ENSEMBLE OF ALL

1058
00:38:59,680 --> 00:39:03,760
THE GENES THAT GET O UP OR DOWN

1059
00:39:03,760 --> 00:39:04,840
REGULATED IN INDIVIDUAL CELLS

1060
00:39:04,840 --> 00:39:06,600
AND WE SET OUT TO DO THIS FOR

1061
00:39:06,600 --> 00:39:08,240
THE SPINAL MOTOR NEURONS.

1062
00:39:08,240 --> 00:39:09,600
THE FIRST STEP WAS ACTUALLY JUST

1063
00:39:09,600 --> 00:39:12,160
TO CHARACTERIZE THE MOTOR NEURON

1064
00:39:12,160 --> 00:39:14,160
SUBTYPES IN THE HEALTHY ADULT

1065
00:39:14,160 --> 00:39:14,520
MOUSE.

1066
00:39:14,520 --> 00:39:16,200
AND SO FOR THIS, WE'VE USED

1067
00:39:16,200 --> 00:39:19,120
SINGLE CELL SEQUENCING, AND THIS

1068
00:39:19,120 --> 00:39:22,400
STUDY WAS PUBLISHED LAST YEAR BY

1069
00:39:22,400 --> 00:39:23,840
THIS TEAM OF GRADUATE STUDENTS

1070
00:39:23,840 --> 00:39:26,720
IN THE LAB, AND OUR ULTIMATE

1071
00:39:26,720 --> 00:39:28,280
GOAL WOULD BE TO USE THIS TYPE

1072
00:39:28,280 --> 00:39:29,360
OF PROFILING THAT I'M GOING TO

1073
00:39:29,360 --> 00:39:32,640
SHOW YOU TO FOLLOW

1074
00:39:32,640 --> 00:39:33,800
TRANSCRIPTOMIC ALTERATIONS IN

1075
00:39:33,800 --> 00:39:35,760
INDIVIDUAL MOTOR NEURONS DURING

1076
00:39:35,760 --> 00:39:36,920
DISEASE PROGRESSION OR INDEED

1077
00:39:36,920 --> 00:39:37,480
AFTER INJURY.

1078
00:39:37,480 --> 00:39:41,320
SO THE STRATEGY THAT WE EMPLOYED

1079
00:39:41,320 --> 00:39:44,000
WAS TO USE A MOUSE LINE IN WHICH

1080
00:39:44,000 --> 00:39:47,160
THE SPINAL MOTOR NEURONS ARE

1081
00:39:47,160 --> 00:39:48,800
LABELED BY A NUCLEAR REPORTER,

1082
00:39:48,800 --> 00:39:51,240
SO THESE ARE THE GREEN NUCLEI

1083
00:39:51,240 --> 00:39:57,480
THAT YOU'RE SEEING HERE IN THIS

1084
00:39:57,480 --> 00:39:58,040
CLEAR SPINAL CORD.

1085
00:39:58,040 --> 00:40:00,040
THIS ALLOWS US TO ENRICH FOR

1086
00:40:00,040 --> 00:40:02,800
THIS POPULATION WITHIN THE

1087
00:40:02,800 --> 00:40:04,080
SPINAL CORD BECAUSE IT'S ONLY

1088
00:40:04,080 --> 00:40:07,480
ABOUT 1% OF ALL OF THE NEURONS.

1089
00:40:07,480 --> 00:40:08,720
 -- SORRY -- ALL THE CELLS IN

1090
00:40:08,720 --> 00:40:09,120
THE SPINAL CORD.

1091
00:40:09,120 --> 00:40:11,440
AND SO IF WE DON'T DO THIS, WE

1092
00:40:11,440 --> 00:40:12,960
FAIL TO ENRICH THIS POPULATION

1093
00:40:12,960 --> 00:40:16,080
ENOUGH TO SEE SUFFICIENT NUMBERS

1094
00:40:16,080 --> 00:40:16,520
OF THEM.

1095
00:40:16,520 --> 00:40:20,360
WHAT WE DID WAS WE SEPARATELY

1096
00:40:20,360 --> 00:40:22,080
SEQUENCED THREE REGIONS OF THE

1097
00:40:22,080 --> 00:40:23,960
SPINAL CORD.

1098
00:40:23,960 --> 00:40:25,040
SO THIS WAS OUR WORKFLOW.

1099
00:40:25,040 --> 00:40:27,360
WE HARVESTED THE TISSUE, WE

1100
00:40:27,360 --> 00:40:29,640
HOMOGENIZED THE TISSUE AND WE

1101
00:40:29,640 --> 00:40:33,920
ISOLATED NUCLEI THAT WE FACT

1102
00:40:33,920 --> 00:40:34,920
SORTED IN ORDER TO SELECT FOR

1103
00:40:34,920 --> 00:40:37,080
THE ONES SELECTING GFP, WHICH

1104
00:40:37,080 --> 00:40:41,400
AGAIN WAS UNDER THE CONTROL

1105
00:40:41,400 --> 00:40:42,520
OF -- BASICALLY WHICH IS ONLY

1106
00:40:42,520 --> 00:40:44,560
EXPRESSED IN THE CHOLINERGIC

1107
00:40:44,560 --> 00:40:46,320
CELLS.

1108
00:40:46,320 --> 00:40:47,720
AND JUST TO POINT OUT HERE THAT

1109
00:40:47,720 --> 00:40:49,080
WHEN WE USE THIS APPROACH, WE'RE

1110
00:40:49,080 --> 00:40:51,360
NOT JUST ENRICHING FOR THE

1111
00:40:51,360 --> 00:40:52,560
SKELETAL MOTOR NEURONS WHICH WE

1112
00:40:52,560 --> 00:40:55,560
WERE MOST INTERESTED IN, BUT WE

1113
00:40:55,560 --> 00:40:58,520
ALSO WOULD BE PURIFYING

1114
00:40:58,520 --> 00:41:00,360
INTERNEURONS THAT ARE

1115
00:41:00,360 --> 00:41:05,840
CHOLINERGIC, AS WELL AS

1116
00:41:05,840 --> 00:41:06,600
PREGANGLIONIC CELLS AS WELL AS

1117
00:41:06,600 --> 00:41:07,520
MOTOR NEURONS.

1118
00:41:07,520 --> 00:41:09,800
SO THE DATA LOOK LIKE THIS.

1119
00:41:09,800 --> 00:41:13,760
THIS IS A REPRESENTATION OF

1120
00:41:13,760 --> 00:41:16,080
SINGLE NUCLEUS TRANSCRIPTOMICS,

1121
00:41:16,080 --> 00:41:20,440
AND EACH DOT IN THIS

1122
00:41:20,440 --> 00:41:21,880
REPRESENTATION CORRESPONDS TO

1123
00:41:21,880 --> 00:41:23,160
ONE NUCLEUS OF A CHOLINERGIC

1124
00:41:23,160 --> 00:41:27,160
CELL THAT WE HAVE SEQUENCED.

1125
00:41:27,160 --> 00:41:28,440
AND THEN THE PROXIMITY OF TWO

1126
00:41:28,440 --> 00:41:31,880
DOTS TO ONE ANOTHER ON THIS

1127
00:41:31,880 --> 00:41:33,600
GRAPH REPRESENTS THEIR

1128
00:41:33,600 --> 00:41:34,840
TRANSCRIPTIONAL SIMILARITY, SO

1129
00:41:34,840 --> 00:41:36,800
THIS IS BASICALLY MAPPING A

1130
00:41:36,800 --> 00:41:39,320
RELATIONSHIP OF EACH CELL TO

1131
00:41:39,320 --> 00:41:42,840
ANOTHER USING THE FULL

1132
00:41:42,840 --> 00:41:45,680
REPERTOIRE OF GENES THAT ARE

1133
00:41:45,680 --> 00:41:46,880
DETECTED IN EACH CELL.

1134
00:41:46,880 --> 00:41:48,000
SO WHAT YOU CAN SEE HERE ARE

1135
00:41:48,000 --> 00:41:49,760
THESE CLUSTERS THAT ARE

1136
00:41:49,760 --> 00:41:50,640
COLOR-CODED WHICH WOULD

1137
00:41:50,640 --> 00:41:53,280
CORRESPOND TO THE DIFFERENT

1138
00:41:53,280 --> 00:41:54,600
SUBTYPES OF SPINAL CHOLINERGIC

1139
00:41:54,600 --> 00:41:56,000
NEURONS THAT WE DISCOVERED.

1140
00:41:56,000 --> 00:41:59,960
USING A COMBINATION OF A FEW

1141
00:41:59,960 --> 00:42:01,400
EXISTING KNOWN MARKERS AND THEN

1142
00:42:01,400 --> 00:42:04,800
SOME ITERATIVE LOOKING AT GENES

1143
00:42:04,800 --> 00:42:05,800
THEY EXPRESSED AND GOING TO SEE

1144
00:42:05,800 --> 00:42:08,080
IN THE TISSUE WHERE THESE WERE

1145
00:42:08,080 --> 00:42:10,040
LOCATED, WE DETERMINED THAT

1146
00:42:10,040 --> 00:42:11,800
THESE WERE THE POPULATIONS OF

1147
00:42:11,800 --> 00:42:14,360
SKELETAL MOTOR NEURONS AND THAT

1148
00:42:14,360 --> 00:42:18,080
THERE WAS QUITE A DIVERSE

1149
00:42:18,080 --> 00:42:20,560
POPULATION OF PREGANGLIONIC

1150
00:42:20,560 --> 00:42:21,640
CELLS, AND THEN THE REMAINING

1151
00:42:21,640 --> 00:42:24,240
ONES WE HAVE HERE ALL CORRESPOND

1152
00:42:24,240 --> 00:42:25,520
TO CHOLINERGIC INTERNEURONS

1153
00:42:25,520 --> 00:42:26,840
WHICH WAS REALLY SURPRISING

1154
00:42:26,840 --> 00:42:28,120
BECAUSE ONLY ONE OR TWO TYPES

1155
00:42:28,120 --> 00:42:29,960
HAD EVER BEEN DESCRIBED BEFORE.

1156
00:42:29,960 --> 00:42:31,520
SO WHAT WE CAN USE THIS KIND OF

1157
00:42:31,520 --> 00:42:34,360
DATA FOR IS TO QUERY IT FOR

1158
00:42:34,360 --> 00:42:37,640
WHICH THE TOP MARKERS OF EACH

1159
00:42:37,640 --> 00:42:38,200
TYPE.

1160
00:42:38,200 --> 00:42:40,480
SO ONE EXAMPLE I'M GOING TO SHOW

1161
00:42:40,480 --> 00:42:41,520
YOU HERE, ON THIS GRAPH YOU HAVE

1162
00:42:41,520 --> 00:42:45,000
A LIST OF GENES AND THEN THE

1163
00:42:45,000 --> 00:42:46,520
SIZE OF THE CIRCLE SHOWS YOU

1164
00:42:46,520 --> 00:42:49,080
WHAT PERCENTAGE OF THAT CELL

1165
00:42:49,080 --> 00:42:50,840
TYPE EXPRESSES A GIVEN GENE, SO

1166
00:42:50,840 --> 00:42:53,880
IN THIS CASE TNS1 WAS VERY

1167
00:42:53,880 --> 00:42:55,160
WIDELY EXPRESSED IN SKELETAL

1168
00:42:55,160 --> 00:42:58,520
MOTOR NEURONS BUT NOT IN THE

1169
00:42:58,520 --> 00:43:00,280
OTHER TWO TYPES, SO TNS1 WOULD

1170
00:43:00,280 --> 00:43:04,360
BE PREDICTED TO BE A REALLY GOOD

1171
00:43:04,360 --> 00:43:04,680
MARKER.

1172
00:43:04,680 --> 00:43:06,640
SO WHAT YOU CAN SEE HERE IS A

1173
00:43:06,640 --> 00:43:10,400
DIFFERENT REPRESENTATION OF TNSL

1174
00:43:10,400 --> 00:43:12,600
MOTOR NEURONS AND IF WE DO

1175
00:43:12,600 --> 00:43:13,480
HYBRIDIZATION FOR THIS GENE, YOU

1176
00:43:13,480 --> 00:43:16,200
CAN SEE THAT IT'S REVEALING

1177
00:43:16,200 --> 00:43:17,640
MOTOR NEURONS IN THE VENTRAL

1178
00:43:17,640 --> 00:43:19,960
HORN OF THE SPINAL CORD.

1179
00:43:19,960 --> 00:43:22,880
NOW WE WANTED TO FOCUS IN ON THE

1180
00:43:22,880 --> 00:43:24,920
ALPHA MOTOR NEURONS, WHICH ARE

1181
00:43:24,920 --> 00:43:26,680
THE TYPE OF MOTOR NEURON THAT

1182
00:43:26,680 --> 00:43:29,280
CONTROL MUSCLE CONTRACTION.

1183
00:43:29,280 --> 00:43:31,080
AND IF WE JUST TAKE THAT SUBSET

1184
00:43:31,080 --> 00:43:32,280
AND SUBCLUSTER THEM TO LOOK AT

1185
00:43:32,280 --> 00:43:33,600
WHAT DIFFERENT TYPES OF THEM

1186
00:43:33,600 --> 00:43:36,920
EXIST, WE COULD DETECT MULTIPLE

1187
00:43:36,920 --> 00:43:37,960
TYPES.

1188
00:43:37,960 --> 00:43:43,880
AND IN ORDER TO KNOW WHICH ONE

1189
00:43:43,880 --> 00:43:46,880
CORRESPONDED TO WHICH, WE

1190
00:43:46,880 --> 00:43:48,200
EMPLOYED A BACK LABELING METHOD

1191
00:43:48,200 --> 00:43:50,400
IN WHICH WE WOULD INJECT A

1192
00:43:50,400 --> 00:43:52,240
PARTICULAR MUSCLE WITH A TRASER.

1193
00:43:52,240 --> 00:43:55,520
THE TRASER IS TAKEN UP AND WILL

1194
00:43:55,520 --> 00:43:57,520
LABEL THE CELL BODY THAT WE

1195
00:43:57,520 --> 00:43:59,400
COULD DETECT IN THE SPINAL CORD

1196
00:43:59,400 --> 00:44:03,000
IN SECTIONS.

1197
00:44:03,000 --> 00:44:06,200
THEN WE COULD OVERLAY ON TOP OF

1198
00:44:06,200 --> 00:44:08,840
THIS IN SITU HYBRIDIZATION FOR

1199
00:44:08,840 --> 00:44:10,240
ALPHA MOTOR NEURON MARKERS AND

1200
00:44:10,240 --> 00:44:11,560
DIFFERENT MARKERS FOR THE

1201
00:44:11,560 --> 00:44:12,760
DIFFERENT SUBTYPES OF ALPHA

1202
00:44:12,760 --> 00:44:17,800
MOTOR NEURONS THAT WE DETECTED.

1203
00:44:17,800 --> 00:44:18,880
SO ONE REALLY INTERESTING THING

1204
00:44:18,880 --> 00:44:20,360
WE DISCOVERED WAS THAT THERE WAS

1205
00:44:20,360 --> 00:44:21,680
A PARTICULAR SUBTYPE THAT WAS

1206
00:44:21,680 --> 00:44:23,760
PRESENT ONLY IN THE CERVICAL

1207
00:44:23,760 --> 00:44:25,440
REGION, BUT NOT REALLY IN

1208
00:44:25,440 --> 00:44:27,600
THORACIC OR IN THE LUMBOSACRAL

1209
00:44:27,600 --> 00:44:28,480
AREA, AND WE THOUGHT THIS WOULD

1210
00:44:28,480 --> 00:44:30,680
BE A REALLY GOOD CANDIDATE FOR

1211
00:44:30,680 --> 00:44:31,800
PHRENIC MOTOR NEURONS WHICH

1212
00:44:31,800 --> 00:44:37,520
CONTROL THE DIE T TH THE DIAPHR,

1213
00:44:37,520 --> 00:44:38,600
THEREFORE, CONTROL BREATHING.

1214
00:44:38,600 --> 00:44:40,040
THE BEST MARKER FOR THIS CLUSTER

1215
00:44:40,040 --> 00:44:43,960
THAT WAS NOT EXPRESSED IN OTHER

1216
00:44:43,960 --> 00:44:49,360
CLUSTERS WAS THE GENE ERB4.

1217
00:44:49,360 --> 00:44:50,800
WE HAVE CIRCLED TWO MOTOR

1218
00:44:50,800 --> 00:44:52,320
NEURONS AS REVEALED BY THIS

1219
00:44:52,320 --> 00:44:54,960
MARKER FOR ALPHA MOTOR NEURONS

1220
00:44:54,960 --> 00:44:57,040
THAT WE HAD DISCOVERED AND WE

1221
00:44:57,040 --> 00:45:01,040
DETECTED IN THESE CELLS THAT

1222
00:45:01,040 --> 00:45:02,760
ERBB4, THE BEST MARKER FOR THIS

1223
00:45:02,760 --> 00:45:05,880
CLUSTER NUMBER 7 WAS INDEED

1224
00:45:05,880 --> 00:45:10,120
EXPRESSED WHEN WE HAD LABELED

1225
00:45:10,120 --> 00:45:12,520
PHRENIC MOTOR NEURONS USING A

1226
00:45:12,520 --> 00:45:13,320
TRANSTHORACIC INJECTION OF OUR

1227
00:45:13,320 --> 00:45:19,000
BLUE MARKER HERE.

1228
00:45:19,000 --> 00:45:20,560
SO IN ADDITIONAL WORK, WE KIND

1229
00:45:20,560 --> 00:45:24,280
OF IDENTIFIED THIS OTHER CLUSTER

1230
00:45:24,280 --> 00:45:27,280
AS INNOVATING DIGITS.

1231
00:45:27,280 --> 00:45:28,600
AND SO WHAT WE THINK HERE IS

1232
00:45:28,600 --> 00:45:32,960
THAT THE SUBTYPES OF ALPHA MOTOR

1233
00:45:32,960 --> 00:45:35,440
NEURONS WE SEE CORRESPOND TO

1234
00:45:35,440 --> 00:45:37,280
SPECIFIC MOTOR POOLS THAT

1235
00:45:37,280 --> 00:45:38,800
INNERVATE SPECIFIC TYPES OF

1236
00:45:38,800 --> 00:45:39,120
MUSCLES.

1237
00:45:39,120 --> 00:45:41,280
AND THIS IS REALLY INTERESTING

1238
00:45:41,280 --> 00:45:43,960
AND RELEVANT TO DISEASES SUCH AS

1239
00:45:43,960 --> 00:45:46,360
ALS BECAUSE THIS NEURONAL

1240
00:45:46,360 --> 00:45:49,360
POPULATION IS RELATIVELY

1241
00:45:49,360 --> 00:45:55,400
RESILIENT IN DISEASE BUT THEN

1242
00:45:55,400 --> 00:45:56,600
ULTIMATELY THE LOSS OF FRENK

1243
00:45:56,600 --> 00:45:57,800
MOTOR NEURON FUNCTION LEADS TO

1244
00:45:57,800 --> 00:46:03,760
THE DEATH OF THE PATIENTS.

1245
00:46:03,760 --> 00:46:06,200
AN INTERESTING THING TO NOTE IS

1246
00:46:06,200 --> 00:46:07,760
THAT RECENT STUDIES HAVE

1247
00:46:07,760 --> 00:46:09,640
ACTUALLY DETECTED MUTATIONS IN

1248
00:46:09,640 --> 00:46:12,280
THIS GENE ERBB4 AND SUGGESTED

1249
00:46:12,280 --> 00:46:15,120
THAT THEY COULD CAUSE ALS, AND

1250
00:46:15,120 --> 00:46:16,560
INTERESTINGLY, THE TYPE OF ALS

1251
00:46:16,560 --> 00:46:20,640
THAT THEY CAUSE IS RESPIRATORY

1252
00:46:20,640 --> 00:46:24,280
ONSET ALS, MEANING A TYPE OF ALS

1253
00:46:24,280 --> 00:46:25,920
IN WHICH THE ABILITY TO BREATHE

1254
00:46:25,920 --> 00:46:30,000
IS AFFECTED EARLIER AS OPPOSED

1255
00:46:30,000 --> 00:46:36,240
TO LIMBS BEING AFFECTED FIRST.

1256
00:46:36,240 --> 00:46:39,080
SO WE DEPOSITED THESE DATA HERE,

1257
00:46:39,080 --> 00:46:40,840
SO JUST TO SAY WE HAVE A LOT OF

1258
00:46:40,840 --> 00:46:43,800
ONGOING WORK IN THIS AREA IN

1259
00:46:43,800 --> 00:46:45,800
TERMS OF NOW APPLYING THIS

1260
00:46:45,800 --> 00:46:47,320
TECHNIQUE BECAUSE THIS WHOLE

1261
00:46:47,320 --> 00:46:53,240
STUDY WAS JUST CREATING AN ATLAS

1262
00:46:53,240 --> 00:46:54,800
OF HEALTHY NEURONS, AND NOW WE

1263
00:46:54,800 --> 00:46:56,360
WANT TO APPLY THIS IN THE

1264
00:46:56,360 --> 00:47:01,280
CONTEXT OF DISEASE AND AXON

1265
00:47:01,280 --> 00:47:01,600
DAMAGE.

1266
00:47:01,600 --> 00:47:06,320
SO I JUST WANT TO END ON A THIRD

1267
00:47:06,320 --> 00:47:07,320
LITTLE VIGNETTE OF SOME WORK

1268
00:47:07,320 --> 00:47:08,720
THAT WE HAVE ONGOING RIGHT NOW

1269
00:47:08,720 --> 00:47:13,600
IN WHICH WE ARE STUDYING THE DLK

1270
00:47:13,600 --> 00:47:14,800
PATHWAY BUT FOR THE FIRST TIME

1271
00:47:14,800 --> 00:47:19,280
IN HUMAN NEURONS, SO RELATIVELY

1272
00:47:19,280 --> 00:47:21,080
LITTLE IS ACTUALLY KNOWN ABOUT

1273
00:47:21,080 --> 00:47:22,840
HOW CONSERVED ALL OF THIS IS IN

1274
00:47:22,840 --> 00:47:24,920
HUMAN NEURONS.

1275
00:47:24,920 --> 00:47:26,320
SO THE PLATFORM THAT WE'RE USING

1276
00:47:26,320 --> 00:47:31,080
IS IPSC-DERIVED NEURONS, THANKS

1277
00:47:31,080 --> 00:47:33,240
TO OUR COLLABORATOR MICHAEL WARD

1278
00:47:33,240 --> 00:47:35,160
IN NINDS WHO'S PROVIDED US WITH

1279
00:47:35,160 --> 00:47:37,040
THIS KIND OF IPSC NEURON THAT'S

1280
00:47:37,040 --> 00:47:42,840
KIND OF PROGRAMMED TO EXPRESS

1281
00:47:42,840 --> 00:47:46,360
NEUROGENIN2, AND THIS YIELDS A

1282
00:47:46,360 --> 00:47:47,800
GLUTAMATERGIC TYPE OF NEURON

1283
00:47:47,800 --> 00:47:48,840
THAT RESEMBLES A CORTICAL

1284
00:47:48,840 --> 00:47:50,080
NEURON.

1285
00:47:50,080 --> 00:47:53,720
AND THIS WORK IS BEING LED BY A

1286
00:47:53,720 --> 00:47:58,680
POSTDOC IN THE LAB, JORGE GOMEZ

1287
00:47:58,680 --> 00:48:06,440
GOMEZ-D EEEZA.

1288
00:48:06,440 --> 00:48:07,560
I'M JUST GOING TO SHOW YOU AN

1289
00:48:07,560 --> 00:48:10,000
EXAMPLE OF A VERY EARLY TRIAL

1290
00:48:10,000 --> 00:48:12,400
WHERE JORGE KIND OF WAS REALLY

1291
00:48:12,400 --> 00:48:14,520
EXCITED TO FIND A MICROSCOPE

1292
00:48:14,520 --> 00:48:16,920
THAT WE COULD USE, AND TO DO

1293
00:48:16,920 --> 00:48:20,080
THESE EXPERIMENTS, AND HE GOT

1294
00:48:20,080 --> 00:48:21,800
REALLY A LITTLE OVERZEALOUS

1295
00:48:21,800 --> 00:48:23,120
HERE, BUT YOU CAN SEE THIS IS

1296
00:48:23,120 --> 00:48:26,000
HOW HE SHOOTS THE AXONS.

1297
00:48:26,000 --> 00:48:28,080
NOWF WE HAVE THIS KIND OF MORE

1298
00:48:28,080 --> 00:48:29,120
CAREFULLY CALIBRATED, BUT WE CAN

1299
00:48:29,120 --> 00:48:31,200
DO THIS IN A REALLY RELIABLE

1300
00:48:31,200 --> 00:48:35,440
MANNER, AND HE DOES THIS IN A

1301
00:48:35,440 --> 00:48:37,000
DISH OF VERY SPARSELY LABELED

1302
00:48:37,000 --> 00:48:38,400
NEURONS SO HE CAN SEE THE

1303
00:48:38,400 --> 00:48:39,880
ENTIRETY, THE NEURONS ARE VERY

1304
00:48:39,880 --> 00:48:41,160
DENSE IN THE DISH BUT HE CAN SEE

1305
00:48:41,160 --> 00:48:44,520
THE ENTIRETY OF ONE WHOLE NEURON

1306
00:48:44,520 --> 00:48:48,680
IF MAYBE ONLY A SMALL FRACTION

1307
00:48:48,680 --> 00:48:50,600
OF THE NEURONS IN A DISH ARE

1308
00:48:50,600 --> 00:48:51,520
EXPRESSING A FLUORESCENT

1309
00:48:51,520 --> 00:48:51,880
PROTEIN.

1310
00:48:51,880 --> 00:48:52,880
SO THAT'S WHAT I'M SHOWING YOU

1311
00:48:52,880 --> 00:48:54,240
HERE IN GRAPHICAL FORMAT.

1312
00:48:54,240 --> 00:48:58,360
YOU CAN ALSO IDENTIFY WHICH AXON

1313
00:48:58,360 --> 00:49:02,760
BELONGS TO WHICH CELL BODY IN

1314
00:49:02,760 --> 00:49:05,120
THIS SYSTEM, SO WE'RE VERY

1315
00:49:05,120 --> 00:49:07,720
INTERESTED IN NOW OBSERVING WHAT

1316
00:49:07,720 --> 00:49:10,560
HAPPENS IN THE AXON THAT'S

1317
00:49:10,560 --> 00:49:14,880
CONNECTED TO THE CELL BODY, AS I

1318
00:49:14,880 --> 00:49:16,200
REFERRED TO IN MY INTRODUCTION.

1319
00:49:16,200 --> 00:49:18,240
AND WHAT HAPPENS IS SHOWN HERE,

1320
00:49:18,240 --> 00:49:21,160
SO THE NEURONS ARE EXPRESSING A

1321
00:49:21,160 --> 00:49:22,480
CYTOPLASMIC RED FLUORESCENT

1322
00:49:22,480 --> 00:49:25,440
PROTEIN, AND YOU CAN SEE THAT

1323
00:49:25,440 --> 00:49:28,880
THE ASTERISK MARKS THE SITE OF

1324
00:49:28,880 --> 00:49:29,880
AXOTOMY, AND YOU CAN SEE THAT

1325
00:49:29,880 --> 00:49:34,320
OVER TIME, THE RED FLUORESCENCE

1326
00:49:34,320 --> 00:49:37,920
IS BEING LOST IN THE DIRECTION

1327
00:49:37,920 --> 00:49:39,840
FROM THE AXOTOMY SITE TO THE

1328
00:49:39,840 --> 00:49:44,120
CELL BODY.

1329
00:49:44,120 --> 00:49:45,400
THESE CELLS ARE ACTUALLY

1330
00:49:45,400 --> 00:49:47,120
UNDERGOING AXON DEGENERATION.

1331
00:49:47,120 --> 00:49:48,160
THIS IS INTERESTING BECAUSE IN

1332
00:49:48,160 --> 00:49:49,520
MOUSE NEURONS, IF YOU DOO THIS

1333
00:49:49,520 --> 00:49:55,440
TO DO THIS TOMOUSE NEURONS IN CE

1334
00:49:55,440 --> 00:50:04,160
PROXIMAL AXON DOESN'T UNDERGO

1335
00:50:04,160 --> 00:50:04,480
DEGENERATION.

1336
00:50:04,480 --> 00:50:05,640
HERE THE ARROWHEAD IS SHOWING

1337
00:50:05,640 --> 00:50:07,400
YOU THE CELL BODY OF A NEURON

1338
00:50:07,400 --> 00:50:10,120
WHOSE AXON WAS CUT, AND THIS

1339
00:50:10,120 --> 00:50:12,320
CELL BODY HERE HAS AN AXON THAT

1340
00:50:12,320 --> 00:50:13,520
WAS UNCUT.

1341
00:50:13,520 --> 00:50:14,960
SO THIS IS WHAT HAPPENS.

1342
00:50:14,960 --> 00:50:16,360
NOW I'M GOING TO PLAY THE VIDEO

1343
00:50:16,360 --> 00:50:18,320
AND THIS IS REALLY SPED UP OVER

1344
00:50:18,320 --> 00:50:21,560
A LONG PERIOD OF TIME, 15 HOURS,

1345
00:50:21,560 --> 00:50:22,960
IN A FEW SECONDS, BUT YOU CAN

1346
00:50:22,960 --> 00:50:24,680
SEE THAT THAT CELL ENDS UP

1347
00:50:24,680 --> 00:50:31,040
DYING.

1348
00:50:31,040 --> 00:50:32,360
WE'RE VERY EXCITED ABOUT THIS

1349
00:50:32,360 --> 00:50:34,360
BECAUSE WE NOW HAVE A HUMAN

1350
00:50:34,360 --> 00:50:36,240
NEURON MODEL THAT UNDERGOES AXON

1351
00:50:36,240 --> 00:50:37,520
DEGENERATION AND CELL DEATH, AND

1352
00:50:37,520 --> 00:50:39,000
I DON'T HAVE TIME TO SHOW YOU

1353
00:50:39,000 --> 00:50:40,880
THIS WORK WHICH IS STILL

1354
00:50:40,880 --> 00:50:42,400
UNPUBLISHED, BUT JORGE HAS

1355
00:50:42,400 --> 00:50:44,320
DISCOVERED A NOVEL SIGNALING

1356
00:50:44,320 --> 00:50:47,920
CASCADE DOWNSTREAM OF DLK THAT

1357
00:50:47,920 --> 00:50:49,560
MEDIATES THIS.

1358
00:50:49,560 --> 00:50:50,960
AND SO I JUST WANT TO FINISH

1359
00:50:50,960 --> 00:50:54,760
WITH A BRIEF SUMMARY THAT I'VE

1360
00:50:54,760 --> 00:50:56,280
SHOWN YOU THAT THERE IS A LINK

1361
00:50:56,280 --> 00:50:59,560
BETWEEN THE AXON DAMAGE RESPONSE

1362
00:50:59,560 --> 00:51:00,120
AND NEUROINFLAMMATION.

1363
00:51:00,120 --> 00:51:01,240
WE THINK THIS COULD BE

1364
00:51:01,240 --> 00:51:02,240
PARTICULARLY RELEVANT IN THE

1365
00:51:02,240 --> 00:51:04,040
CONTEXT OF NEURODEGENERATIVE

1366
00:51:04,040 --> 00:51:06,880
DISEASE IN WHICH WE KNOW THAT

1367
00:51:06,880 --> 00:51:07,760
NEUROINFLAMMATION CAN PLAY

1368
00:51:07,760 --> 00:51:10,080
IMPORTANT ROLES, AND SO AXON

1369
00:51:10,080 --> 00:51:11,280
INJURY SIGNALING NOT ONLY

1370
00:51:11,280 --> 00:51:13,080
IMPACTS THE NEURON ITSELF, BUT

1371
00:51:13,080 --> 00:51:16,120
ALSO THE SURROUNDING TISSUE.

1372
00:51:16,120 --> 00:51:17,640
I'VE ALSO SHOWN YOU HOW WE CAN

1373
00:51:17,640 --> 00:51:20,320
USE SINGLE CELL TRANSCRIPTOMICS

1374
00:51:20,320 --> 00:51:22,400
TO DEFINE CELL TYPES SUCH AS

1375
00:51:22,400 --> 00:51:24,040
SPINAL MOTOR NEURONS, AND HOW WE

1376
00:51:24,040 --> 00:51:26,720
PLAN TO USE THIS TECHNOLOGY TO

1377
00:51:26,720 --> 00:51:28,120
INVESTIGATE HOW NEURON TYPES

1378
00:51:28,120 --> 00:51:29,440
MIGHT DIFFERENTIALLY RESPOND TO

1379
00:51:29,440 --> 00:51:31,520
INJURY.

1380
00:51:31,520 --> 00:51:33,920
AND WE HAVE ALSO COMPLEMENTED

1381
00:51:33,920 --> 00:51:35,720
WORK IN THE MOUSE MODELS WITH

1382
00:51:35,720 --> 00:51:37,160
STUDIES IN HUMAN NEURONS WHICH

1383
00:51:37,160 --> 00:51:38,640
CAN HELP ACCELERATE TRANSLATION

1384
00:51:38,640 --> 00:51:42,080
OF BASIC RESEARCH TO

1385
00:51:42,080 --> 00:51:42,760
CLINIC-USEFUL KNOWLEDGE.

1386
00:51:42,760 --> 00:51:44,320
AND I REALLY THINK THAT

1387
00:51:44,320 --> 00:51:45,160
FUNDAMENTAL KNOWLEDGE OF THE

1388
00:51:45,160 --> 00:51:48,160
KIND OF BASIC RESEARCH THAT WE

1389
00:51:48,160 --> 00:51:50,440
DO IS ESSENTIAL TO UNDERSTAND

1390
00:51:50,440 --> 00:51:51,560
NEURODEVELOPMENTAL AND

1391
00:51:51,560 --> 00:51:52,480
NEURODEGENERATIVE DISORDERS AND

1392
00:51:52,480 --> 00:51:53,680
ALSO TO DEVELOP CLINICAL

1393
00:51:53,680 --> 00:51:55,800
THERAPIES IN NEUROPROTECTION AND

1394
00:51:55,800 --> 00:51:56,160
NERVE REPAIR.

1395
00:51:56,160 --> 00:51:59,560
SO WITH THAT, I WOULD LIKE TO

1396
00:51:59,560 --> 00:52:00,840
JUST ACKNOWLEDGE THE MEMBERS OF

1397
00:52:00,840 --> 00:52:02,200
MY LAB WHO CONTRIBUTED TO THE

1398
00:52:02,200 --> 00:52:04,440
WORK THAT I SHARED TODAY.

1399
00:52:04,440 --> 00:52:09,240
I'VE UNDERLINED THEIR NAMES, AND

1400
00:52:09,240 --> 00:52:15,160
ALSO THANK ME MIE COLLABORATO ME

1401
00:52:15,160 --> 00:52:16,920
AT THE NIH INTRAMURAL PROGRAM.

1402
00:52:16,920 --> 00:52:17,600
THANK YOU VERY MUCH FOR YOUR

1403
00:52:17,600 --> 00:52:20,320
ATTENTION.

1404
00:52:20,320 --> 00:52:25,840
>>THANK YOU, DR. LE
PICHON AND

1405
00:52:25,840 --> 00:52:27,040
DR. NARENDRA FOR SHARING YOUR

1406
00:52:27,040 --> 00:52:28,920
FASCINATING BODY OF WORK IN

1407
00:52:28,920 --> 00:52:30,360
OFFERING DEEPER INSIGHTS IN THE

1408
00:52:30,360 --> 00:52:31,240
UNDERSTANDING OF CELLULAR

1409
00:52:31,240 --> 00:52:33,640
MECHANISMS AND MODELS FOR NEURAL

1410
00:52:33,640 --> 00:52:35,840
DEGENERATION.

1411
00:52:35,840 --> 00:52:37,000
WE HAVE TIME FOR A FEW

1412
00:52:37,000 --> 00:52:38,120
QUESTIONS.

1413
00:52:38,120 --> 00:52:39,600
THE FIRST QUESTION IS ACTUALLY

1414
00:52:39,600 --> 00:52:44,880
FOR DR. NARENDRA.

1415
00:52:44,880 --> 00:52:46,560
SO, FANTASTIC LECTURE.

1416
00:52:46,560 --> 00:52:48,520
DO WE HAVE A MECHANISM FOR CHRIS

1417
00:52:48,520 --> 00:52:55,920
CRISTAE BECOMING -- OUTSIDE OF

1418
00:52:55,920 --> 00:52:56,560
MITOCHONDRIAL MEMBRANE?

1419
00:52:56,560 --> 00:52:58,640
IS THERE A MEMBRANE DISORDER OR

1420
00:52:58,640 --> 00:53:01,400
MEMBRANE MITOCHONDRIAL

1421
00:53:01,400 --> 00:53:04,000
DISRUPTION IN ALS OR

1422
00:53:04,000 --> 00:53:04,560
PARKINSON'S-TYPE DISEASE?

1423
00:53:04,560 --> 00:53:06,480
>>SO SORRY, I MISSED THE
FIRST

1424
00:53:06,480 --> 00:53:07,480
PART OF THAT QUESTION.

1425
00:53:07,480 --> 00:53:10,000
>>DO WE HAVE A MECHANISM
FOR

1426
00:53:10,000 --> 00:53:15,560
THE MITOCHONDRIAL CRISTAE

1427
00:53:15,560 --> 00:53:17,840
BECOMING FUSEOGENIC FROM THE

1428
00:53:17,840 --> 00:53:19,440
MITOCHONDRIAL MEMBRANE, AND THE

1429
00:53:19,440 --> 00:53:22,200
SECRETARY PART IS THERE SOME

1430
00:53:22,200 --> 00:53:24,200
SORT SORT OF MEMBRANE

1431
00:53:24,200 --> 00:53:25,600
MITOCHONDRIAL DISRUPTION IN ALS.

1432
00:53:25,600 --> 00:53:27,480
>>SO I THINK TO TAKE THE
SECOND

1433
00:53:27,480 --> 00:53:29,720
PART OF THE QUESTION FIRST IN

1434
00:53:29,720 --> 00:53:31,920
PARKINSON'S DISEASE AND ALS, I

1435
00:53:31,920 --> 00:53:33,160
THINK THERE ARE OFTEN STRUCTURAL

1436
00:53:33,160 --> 00:53:36,760
CHANGES THAT ARE SEEN TO THE MY

1437
00:53:36,760 --> 00:53:47,400
TOE DONEMITOCHONDRIA THAT I SHOU

1438
00:53:47,400 --> 00:53:47,640
BEFORE.

1439
00:53:47,640 --> 00:53:49,440
I'M NOT SURE I ENTIRELY

1440
00:53:49,440 --> 00:53:51,480
UNDERSTAND THE FIRST QUESTION.

1441
00:53:51,480 --> 00:53:53,640
THERE'S AN OUTER MEMBRANE OF THE

1442
00:53:53,640 --> 00:53:55,680
MITOCHONDRIA AND INNER MEMBRANE

1443
00:53:55,680 --> 00:53:58,200
AND FUSION OF THE OUTER MEMBRANE

1444
00:53:58,200 --> 00:54:06,120
IS MEDIATED BY THESE -- IT'S

1445
00:54:06,120 --> 00:54:09,400
PROBABLY THE INNER MEMBRANE HAS

1446
00:54:09,400 --> 00:54:10,600
CRISTAE COMPONENT AND ALSO THIS

1447
00:54:10,600 --> 00:54:14,600
BOUNDARY COMPONENT, AND I THINK

1448
00:54:14,600 --> 00:54:16,200
OPA1 IS KIND OF ON THAT BOUNDARY

1449
00:54:16,200 --> 00:54:17,800
CLOSE TO THE CRISTAE JUNCTION,

1450
00:54:17,800 --> 00:54:19,200
SO PROBABLY THE FUSION DOESN'T

1451
00:54:19,200 --> 00:54:21,000
HAPPEN WHERE THE CRISTAE IS, PER

1452
00:54:21,000 --> 00:54:22,440
SE, BUT PROBABLY HAPPENS SORT OF

1453
00:54:22,440 --> 00:54:25,840
ADJACENT TO THE CRISTAE.

1454
00:54:25,840 --> 00:54:28,440
>>OKAY, THANK YOU.

1455
00:54:28,440 --> 00:54:32,680
FOR DR. LE PICHON, WHEN THE DLK

1456
00:54:32,680 --> 00:54:34,600
STRESS PATHWAY IS TURNED ON IN

1457
00:54:34,600 --> 00:54:35,600
NEURONS OF THE BRAIN, DOES IT

1458
00:54:35,600 --> 00:54:38,920
MEAN THAT THOSE CELLS ARE COMMIT

1459
00:54:38,920 --> 00:54:41,600
TODAY DIE?

1460
00:54:41,600 --> 00:54:45,280
>>SO WE THINK BASED ON
OUR --

1461
00:54:45,280 --> 00:54:48,240
WELL, SO I THINK SOME MORE

1462
00:54:48,240 --> 00:54:49,880
RESEARCH IS NEEDED, BUT BASED ON

1463
00:54:49,880 --> 00:54:52,800
WHAT WE HAVE SEEN SO FAR WITH

1464
00:54:52,800 --> 00:54:54,120
THE PERIPHERAL -- THE PERIPHERY

1465
00:54:54,120 --> 00:54:58,480
PROJECTING NEURONS AND THEN

1466
00:54:58,480 --> 00:55:00,840
THIS -- SO THE DRG NEWER YONS

1467
00:55:00,840 --> 00:55:02,160
AND MOTOR NEURONS, WHEN WE DO

1468
00:55:02,160 --> 00:55:03,480
THOSE KINDS OF INJURIES IN THE

1469
00:55:03,480 --> 00:55:05,800
MOUSE, THOSE CELLS DO NOT DIE

1470
00:55:05,800 --> 00:55:07,400
AFTER AXON DAMAGE.

1471
00:55:07,400 --> 00:55:10,760
HOWEVER, WE'RE REALLY CURIOUS

1472
00:55:10,760 --> 00:55:11,520
ABOUT WHAT HAPPENS IN BRAIN

1473
00:55:11,520 --> 00:55:13,080
CELLS BASED ON OUR EXPERIMENTS

1474
00:55:13,080 --> 00:55:17,160
OF THE HUMAN NEURONS IN VITRO.

1475
00:55:17,160 --> 00:55:24,240
SO I WOULD PREDICT YES, ONLY

1476
00:55:24,240 --> 00:55:26,000
BECAUSE OF THE REDUCED CAPACITY

1477
00:55:26,000 --> 00:55:27,760
OF CENTRAL NERVOUS SYSTEM

1478
00:55:27,760 --> 00:55:29,120
NEURONS TO REGENERATE, BUT I

1479
00:55:29,120 --> 00:55:29,800
DON'T REALLY KNOW.

1480
00:55:29,800 --> 00:55:31,760
AND I THINK LOOKING AT HOW -- AT

1481
00:55:31,760 --> 00:55:33,560
THE IPT PLAY BETWEEN ABILITY TO

1482
00:55:33,560 --> 00:55:35,240
REPAIR AND A SURVIVAL IS ALSO AN

1483
00:55:35,240 --> 00:55:37,640
INTERESTING QUESTION.

1484
00:55:37,640 --> 00:55:41,080
>>THANK YOU.

1485
00:55:41,080 --> 00:55:43,040
FOR DR. NARENDRA, ANOTHER

1486
00:55:43,040 --> 00:55:43,840
QUESTION.

1487
00:55:43,840 --> 00:55:47,960
YOU'D MENTIONED ABOUT THE

1488
00:55:47,960 --> 00:55:48,840
DIVERSE PHENOTYPES IN

1489
00:55:48,840 --> 00:55:50,960
INDIVIDUALS WITH CHCHD10

1490
00:55:50,960 --> 00:55:51,520
MUTATIONS.

1491
00:55:51,520 --> 00:55:52,600
WHAT ACCOUNTS FOR THE DIVERSITY

1492
00:55:52,600 --> 00:55:56,200
OF THOSE PHENOTYPES?

1493
00:55:56,200 --> 00:55:58,560
>>WE DON'T FULLY
UNDERSTAND IT,

1494
00:55:58,560 --> 00:56:01,960
BUT MY SUSPICION IS THAT THESE

1495
00:56:01,960 --> 00:56:02,920
MUTATIONS ARE CAUSING THE

1496
00:56:02,920 --> 00:56:05,840
PROTEINS TO MISFOLD IN DIFFERENT

1497
00:56:05,840 --> 00:56:09,080
WAYS, AND JUST LIKE IN DIFFERENT

1498
00:56:09,080 --> 00:56:12,480
FORMS OF TAUOPATHY, YOU CAN GET

1499
00:56:12,480 --> 00:56:14,080
ONE NEUROLOGICAL DISEASE VERSUS

1500
00:56:14,080 --> 00:56:16,080
ANOTHER DEPENDING ON WE NOW KNOW

1501
00:56:16,080 --> 00:56:17,600
DIFFERENT STRAINS -- DIFFERENT

1502
00:56:17,600 --> 00:56:20,520
WAYS IN WICHITA IS MISFORMED.

1503
00:56:20,520 --> 00:56:21,840
SAME THING SEEMS TO BE TRUE

1504
00:56:21,840 --> 00:56:23,760
ABOUT ALPHA SYNUCLEIN THAT

1505
00:56:23,760 --> 00:56:25,560
MISFOLDS IN PARKINSON DISEASE

1506
00:56:25,560 --> 00:56:27,200
AND ANOTHER DISEASE CALLED

1507
00:56:27,200 --> 00:56:28,320
MULTIPLE SYSTEM ATROPHY.

1508
00:56:28,320 --> 00:56:30,200
I THINK PERHAPS IN THE SAME WAY

1509
00:56:30,200 --> 00:56:32,440
THESE ARE CAUSING C10 TO MISFOLD

1510
00:56:32,440 --> 00:56:34,280
IN DIFFERENT WAYS, AND IF IT

1511
00:56:34,280 --> 00:56:35,240
MISFOLDS ONE WAY, IT'S MORE

1512
00:56:35,240 --> 00:56:37,840
TOXIC TO NEURONS AND IF IT

1513
00:56:37,840 --> 00:56:39,280
MISFOLDS ANOTHER WAY, IT'S MORE

1514
00:56:39,280 --> 00:56:41,400
TOXIC TO MUSCLE CELLS.

1515
00:56:41,400 --> 00:56:42,000
>>OKAY.

1516
00:56:42,000 --> 00:56:45,280
THANK YOU.

1517
00:56:45,280 --> 00:56:45,480
FOR --

1518
00:56:45,480 --> 00:56:47,040
>>SO FOR DR. LE PICHON, A

1519
00:56:47,040 --> 00:56:48,320
QUESTION.

1520
00:56:48,320 --> 00:56:50,080
HOW DOES KNOWING THE

1521
00:56:50,080 --> 00:56:51,000
TRANSCRIPTIONAL ABILITY OF

1522
00:56:51,000 --> 00:56:52,640
PARTICULAR NEURONS HELP ADVANCE

1523
00:56:52,640 --> 00:56:53,840
UNDERSTANDING OF

1524
00:56:53,840 --> 00:56:57,280
NEURODEGENERATIVE DISEASES?

1525
00:56:57,280 --> 00:57:01,560
>>SO ONE THING THAT'S
REALLY

1526
00:57:01,560 --> 00:57:03,000
INTERESTING ABOUT DIFFERENT

1527
00:57:03,000 --> 00:57:04,000
NEURODEGENERATIVE DISEASES IS,

1528
00:57:04,000 --> 00:57:08,600
YOU KNOW, EACH ONE WILL HAVE A

1529
00:57:08,600 --> 00:57:10,080
PARTICULAR CONSTELLATION OF

1530
00:57:10,080 --> 00:57:11,920
SYMPTOMS, AND THAT'S PROBABLY

1531
00:57:11,920 --> 00:57:13,560
BECAUSE DIFFERENT NEURON TYPES

1532
00:57:13,560 --> 00:57:15,520
TEND TO BE MORE VULNERABLE THAN

1533
00:57:15,520 --> 00:57:18,680
OTHERS TO THE DIFFERENT -- IN

1534
00:57:18,680 --> 00:57:21,480
THE DIFFERENT DISEASE CONTEXTS.

1535
00:57:21,480 --> 00:57:25,320
SO I THINK THAT UNDERSTANDING

1536
00:57:25,320 --> 00:57:28,400
THE IDENTITY OF THE DIFFERENT

1537
00:57:28,400 --> 00:57:30,080
NEURON TYPES AT THE GET-GO CAN

1538
00:57:30,080 --> 00:57:32,040
KIND OF LAY THE GROUNDWORK FOR

1539
00:57:32,040 --> 00:57:35,800
THEN UNDERSTANDING HOW ONE TYPE

1540
00:57:35,800 --> 00:57:37,360
MIGHT BE MORE VULNERABLE TO A

1541
00:57:37,360 --> 00:57:38,800
CERTAIN TYPE OF STRESS THAN

1542
00:57:38,800 --> 00:57:39,240
ANOTHER, FOR EXAMPLE.

1543
00:57:39,240 --> 00:57:41,000
I THINK THOSE ARE REALLY CLEAR

1544
00:57:41,000 --> 00:57:47,440
EXAMPLE OF THAT IN PARKINSON'S E

1545
00:57:47,440 --> 00:57:48,840
SUBSTANTIA NIGRA NEURONS, FOR

1546
00:57:48,840 --> 00:57:49,120
EXAMPLE.

1547
00:57:49,120 --> 00:57:50,320
AND I THINK, YOU KNOW, THE FIELD

1548
00:57:50,320 --> 00:57:51,360
IS KIND OF MOVING IN THIS

1549
00:57:51,360 --> 00:57:53,080
DIRECTION TO START EXAMINING

1550
00:57:53,080 --> 00:57:54,560
THAT TYPE OF QUESTION.

1551
00:57:54,560 --> 00:57:59,680
>>THANK YOU.

1552
00:57:59,680 --> 00:58:04,360
SO FOR DR. NARENDRA, HOW -- IS

1553
00:58:04,360 --> 00:58:12,000
THE OME1/DELE -- FOR

1554
00:58:12,000 --> 00:58:12,720
MITOCHONDRIAL DYSFUNCTION?

1555
00:58:12,720 --> 00:58:14,680
>>I THINK IT'S STILL NOT

1556
00:58:14,680 --> 00:58:16,320
ENTIRELY CLEAR BUT IT SEEM LIKE

1557
00:58:16,320 --> 00:58:18,840
IT IS PROBABLY GOING TO BE

1558
00:58:18,840 --> 00:58:19,480
PRETTY BROAD.

1559
00:58:19,480 --> 00:58:20,960
SO AT THE END THERE, I MENTIONED

1560
00:58:20,960 --> 00:58:22,320
SORT OF THREE PAPERS THAT HAVE

1561
00:58:22,320 --> 00:58:24,040
BEEN PUBLISHED THIS YEAR,

1562
00:58:24,040 --> 00:58:25,800
INCLUDING OUR PAPER, SO WE HAVE

1563
00:58:25,800 --> 00:58:27,320
KIND OF AN EXAMPLE OF A

1564
00:58:27,320 --> 00:58:28,640
MISFOLDED PROTEIN STRESS THAT

1565
00:58:28,640 --> 00:58:33,840
SEEMS TO ACTIVATE THIS PATHWAY.

1566
00:58:33,840 --> 00:58:35,280
USING THE -- MODEL, WE SHOWED

1567
00:58:35,280 --> 00:58:38,960
THAT IF YOU JUST CAUSE AN --

1568
00:58:38,960 --> 00:58:40,480
DEFECT, YOU ACTIVATE THE SAME

1569
00:58:40,480 --> 00:58:41,680
PATHWAY.

1570
00:58:41,680 --> 00:58:43,520
ANOTHER TWO MODELLS SHOWING IF

1571
00:58:43,520 --> 00:58:45,560
YOU DISRUPT LIPID METABOLISM IN

1572
00:58:45,560 --> 00:58:50,680
THE MITOCHONDRIA TO INTERFERE

1573
00:58:50,680 --> 00:58:51,920
WITH KIND OF THE MEMBRANE, YOU

1574
00:58:51,920 --> 00:58:54,360
GET THE SAME PATHWAY ACTIVATED.

1575
00:58:54,360 --> 00:58:59,080
SO I THINK IT MAY TURN OUT

1576
00:58:59,080 --> 00:59:01,280
THAT -- PREDOMINANT WAY IN WITS

1577
00:59:01,280 --> 00:59:03,240
MITOCHONDRIAL STRESS SIGNALS

1578
00:59:03,240 --> 00:59:09,760
TO -- RESPONSE IN VIVO.

1579
00:59:09,760 --> 00:59:12,040
>>WELL, THAT ACTUALLY
BRINGS US

1580
00:59:12,040 --> 00:59:12,800
UP TO THE HOUR.

1581
00:59:12,800 --> 00:59:14,080
AGAIN, I WANT TO THANK BOTH OF

1582
00:59:14,080 --> 00:59:21,200
YOU FOR YOUR EXCELLENT TALKS OF

1583
00:59:21,200 --> 00:59:22,400
YOUR INVESTIGATIONS TO OUR NIH

1584
00:59:22,400 --> 00:59:22,840
COMMUNITY.

1585
00:59:22,840 --> 00:59:24,200
I WISH ALL OF YOU A WONDERFUL

1586
00:59:24,200 --> 00:59:24,440
AFTERNOON.

1587
00:59:24,440 --> 00:00:00,000
THANK YOU.