>> WELL, GREETINGS AND
SALUTATIONS!
I'M DAN KASTNER, THE SCIENTIFIC
DIRECTOR EMERITUS OF THE
NATIONAL HUMAN GENOME RESEARCH
INSTITUTE AND STILL AN ACTIVE
PHYSICIAN SCIENTIST HERE IN THE
INTRAMURAL RESEARCH PROGRAM OF
NHGRI.
IT IS MY WONDERFUL DELIGHT TO
WELCOME YOU TODAY TO THIS, THE
11TH INSTALLMENT IN THE 2024
SESSIONS OF DEMYSTIFYING
MEDICINE.
A SET OF SESSIONS SET UP TO
BRIDGE THE EXCITING DEVELOPMENTS
IN BIOLOGY AND ENGINEERING WITH
MEDICINE.
AND OF COURSE ALONG THE LINES OF
THE BRIDGE, WE HAVE THE ICONIC
PHOTO OF THE BROOKLYN BRIDGE
SPANNING THE EAST RIVER BETWEEN
MANHATTAN AND, GUESS WHAT,
BROOKLYN!
AND YOU CAN SEE ON THE CATWALK
UP IN THE LEFT-HAND SIDE OF THE
PHOTO TWO GENTLEMEN.
ONE OF THEM I'M SURE FROM
BROOKLYN, THE OTHER FROM
MANHATTAN, WHO WERE DISCUSSING
THE SCIENTIFIC ISSUES OF THE
DAY, BRINGING TOGETHER BASIC
SCIENCE AND CLINICAL MEDICINE.
AND TODAY, WE HAVE A SIMILAR
SUCH SITUATION IN WHICH WE ARE
BRINGING TOGETHER BASIC SCIENCE
AND CLINICAL MEDICINE IN THE
DISCUSSION OF PARKINSON'S
DISEASE, AND WE HAVE ACTUALLY
TWO THIRDS OF THE RECIPIENTS OF
THIS YEAR'S BREAKTHROUGH PRIZE,
MY GOODNESS, JUST TALKING MADE
THE THING GO FORWARD,
BREAKTHROUGH PRIZE THAT WILL BE
AWARDED IN APRIL, THOMAS GASSER
IS THE THIRD RECIPIENT OF THAT,
BUT WE HAVE DR. ANDY SINGLETON
AND DR. ELLEN SIDRANSKY HERE,
WHO ARE GOING TO BE TALKING TO
US ABOUT THE LATEST INFORMATION
BOTH ON THE GENETICS AND
THERAPEUTICS RELATED TO
PARKINSON'S DISEASE.
SO IN ANY CASE, THIS IS A SERIES
OF TALKS THAT OCCURS TUESDAYS,
AS YOU CAN SEE ON THE SLIDE,
FROM 4:00 TO 6:00 P.M., FROM
JANUARY THROUGH MAY.
YOU CAN WATCH ON THE VIDEOCAST
LINK THAT'S SHOWN THERE.
FOR THOSE OF YOU WHO WANT CME
CREDIT, YOU CAN GET IT USING THE
CODE 5296, ANDTHE -- YOU CAN USE
FEEDBACK ON THE VIDEOCAST
DISPLAY TO TURN IN YOUR
QUESTIONS AND WE'RE ACTUALLY
GOING TO HAVE A DIZZYING BACK
AND FORTH OF SPEAKERS TODAY WITH
DR. SINGLETON LEADING OFF AND
THEN DR. SIDRANSKY AND ALL OF
THE QUESTIONS WILL BE SAVED
UNTIL THE END.
ALL OF THE PREVIOUS SESSIONS ARE
ARCHIVED AND YOU CAN GO TO THE
LINK THERE TO SEE THEM AND FOR
ADDITIONAL INFORMATION, THERE'S
AN EMAIL ADDRESS FOR THAT.
AND OF COURSE NOT TO FORGET, WE
HAVE BEEN BRIDGING SILOS AT THE
NIH SINCE 1999.
WE DO NOT WANT TO HAVE SILOS, WE
WANT TO GET PEOPLE TOGETHER, AND
EVEN WITH A FEW CORNY JOKES TO
MAKE THAT HAPPEN.
SO IN ANY EVENT, MORE ON THE CME
INFORMATION, THE CODE AGAIN,
52096.
IN TERMS OF DISCLOSURES,
DR. SIDRANSKY REPORTS GRANT OR
RESEARCH SUPPORT FROM ROCHE, AND
LET'S JUST GET STARTED WITH THE
INTRODUCTIONS OF OUR TWO
SPEAKERS.
FIRST THE GOOD DR. ANDREW
SINGLETON.
HE IS AN NIH DISTINGUISHED
INVESTIGATOR, DIRECTOR OF THE
CENTER FOR ALZHEIMER'S AND
RELATED DEMENTIAS, AND CHIEF OF
THE MOLECULAR GENETICS SECTION
OF THE LABORATORY OF
NEUROGENETICS IN THE NATIONAL
INSTITUTE OF AGING.
HE GOT HIS BACHELOR'S DEGREE
WITH HONORS IN APPLIED
PHYSIOLOGY AT THE UNIVERSITY OF
SUNDERLAND AND DOCTORAL DEGREE
IN NEUROSCIENCE FROM THE
UNIVERSITY OF NEW CASTLE UPON
TYNE IN THE UK.
HE DID HIS DOCTORAL FELLOWSHIP
AT THE MAYO CLINIC IN
JACKSONVILLE, AND HIS LAB WORKS
ON THE JE NE GENETIC BASES OF ME
NEUROLOGIC DISORDERS INCLUDING
MOVEMENT DISORDERS, DEMENTIAS
AND ALS.
HE WAS THE FIRST RE RECIPIENT OF
THE JAY VAN ANDEL AWARD FOR
OUTSTANDING ACHIEVEMENT IN
PARKINSON'S DISEASE RESEARCH,
AND AS I MENTIONED BEFORE, HE'S
THE RECIPIENT, ONE OF THE
RECIPIENTS OF THIS YEAR'S
BREAKTHROUGH PRIZE IN THE LIFE
SCIENCES.
HIS GROUP HAS DISCOVERED A
NUMBER OF GENETIC MUTATIONS THAT
CAUSED PARKINSON'S DISEASE AND
WE'LL HEAR A NUMBER IN HIS TALK
INCLUDING THE ALPHA SYNUCLEIN
MULTIPLICATION MUTATION AND
MUTATIONS IN LRRK2.
AND HE'S A FOUNDING MEMBER OF
THE INTERNATIONAL PARKINSON
DISEASE GENOMICS CONSORTIUM AND
THE GLOBAL PARKINSON'S GENETICS
PROGRAM.
OUR SECOND SPEAKER -- WELL,
ACTUALLY IT WILL BE OUR
SECOND -- IS DR. ELLEN
SIDRANSKY, SENIOR INVESTIGATOR
AND HEAD OF THE MOLECULAR
NEUROGENETICS SECTION AND CHIEF
OF THE MEDICAL GENETICS BRANCH
OF THE NATIONAL HUMAN GENOME
RESEARCH INSTITUTE.
SHE GOT HER BACHELOR'S DEGREE
MAGNA CUM LAUDE IN BIOLOGY FROM
BRANDEIS AND HER MEDICAL DEGREE
FROM TULANE.
SHE DID A RESIDENCY IN
PEDIATRICS AT NORTHWESTERN AND A
FELLOWSHIP HERE AT THE NIH IN
CLINICAL GENETICS.
SHE WAS THE FIRST PERSON, AND
THIS IS REALLY AN ASTUTE
CLINICIAN STORY.
FIRST PERSON TO ESTABLISH THE
RELATIONSHIP BETWEEN
GBA1 MUTATIONS, WHICH CAN CAUSE
GAUCHER DISEASE, AND THE RISK OF
DEVELOPING EITHER PARKINSON'S
DISEASE OR LEWY BODY DEMENTIA.
SHE'S WON A NUMBER OF DIFFERENT
AWARDS INCLUDING THE
BREAKTHROUGH PRIZE AS I
MENTIONED BEFORE AND THE
OVERARCHING GOALS OF HER
RESEARCH GROUP ARE, ONE, TO
ELUCIDATE THE RELATIONSHIP
BETWEEN GLUCOCEREBROSIGH DAYS
AND PARKINSON'S DISEASE TO
IDENTIFY FACTORS THAT CONTRIBUTE
TO CLINICAL HETEROGENEITY AND
SINGLE GENE DISORDERS AND TO
DEVELOP NEW THERAPIES FOR
PATIENTS.
AND WITHOUT FURTHER ADO, I THINK
IT IS TIME FOR US TO WELCOME DR.
DR. SINGLETON, PLEASE.
[APPLAUSE]
>> SO THANKS, IT'S A REAL
PLEASURE TO SPEAK HERE TODAY,
PARTICULARLY WITH ELLEN.
I THINK I GAVE A DEMYSTIFYING
TALK ABOUT 15 OR 16 YEARS AGO,
AND THE REASON I KIND OF
REMEMBERED THAT IT WAS 15 OR 16
IS MY OLD ELLEN SIDRANSKY
DAUGHTER IS 22.
SHE'S A SENIOR AT COLLEGE NOW,
AND I REMEMBER COMING HOME THE
FIRST TIME I GAVE ONE OF THESE
TALKS, SHE WAS ABOUT YEA HIGH
AND SHE HAD A PAD WITH TICS ON
IT, LIKE HUNDREDS OF TICS.
SHE WATCHED THE VIDEO ONLINE AND
SHE SAID I TICKED EVERY TIME YOU
SAID "UM."
SO NOW I'M VERY AWARE, NOT AWARE
ENOUGH BUT VERY AWARE OF SAYING
UM A LOT.
I THINK OF THAT EVERY TIME I
GIVE A TALK.
SO THANK YOU TO THIS LECTURE FOR
MAKING ME THINK OF THAT, AT
LEAST.
SO ELLEN AND I ARE GOING TO HAVE
A BIT OF BACK AND FORTH TODAY.
WE'RE GOING TO TALK ABOUT THE
GENETICS OF PARKINSON'S DISEASE,
AND ACTUALLY HOW THIS FIELD HAS
EVOLVED FROM EARLY GENETIC
DISCOVERIES, AND ACTUALLY THE
FIRST GENETIC DISCOVERY IN
PARKINSON'S DISEASE WAS MADE
HERE AT NIH, THROUGH TO THE
REALIZATION OF THAT GENETICS
WORK WHICH IS AROUND FINDING
THERAPEUTIC TARGETS.
WE'RE GOING TO START QUICKLY
WITHOUT CHANGING SLIDES, ELLEN
IS GOING TO GIVE A LITTLE BIT OF
BACKGROUND ON PARKINSON'S
DISEASE AND THE CLINICAL AND
NEUROPATHOLOGICAL FEATURES OF
PARKINSON'S DISEASE AND THEN
I'LL TAKE YOU THROUGH THE ORDER
OF THE REST OF THE DISCUSSION.
>> THANK YOU.
I ALSO WANT TO ECHO, IT'S GREAT
TO BE HERE TOGETHER WITH ANDY,
IT MAY BE THE FIRST OF MANY.
WE'VE KNOWN EACH OTHER FOR QUITE
A WHILE.
I JUST THOUGHT I WOULD GIVE A
VERY BRIEF CLINICAL OVERVIEW OF
WHAT PARKINSON'S DISEASE IS, MAY
NOT BE.
I'M NEW TO MOST OF THE PEOPLE IN
THE AUDIENCE TODAY, BUT JUST
WANTED TO REVIEW THAT PARKINSON
DISEASE IS REALLY A CLINICALLY
AND PATHOLOGICALLY DEFINED
ENTITY.
IT INCLUDES THE CRITERIA IS YOU
MUST HAVE BRADYKINESIA, WHICH IS
SLOWNESS OF MOVEMENT, AND AT
LEAST ONE OF THE FOLLOWING,
MUSCULAR RIGIDITY, A REST TREMOR
AND POSTURAL INSTABILITY.
THE CARTOON THAT I'VE SHOWN
THAT'S KIND OF A CLASSIC JUST
SHOWS A FEW OF THE OTHER COMMON
FEATURES THAT YOU ENCOUNTER IN
PATIENTS WITH PARKINSON DISEASE.
A TERM THAT WE MAY USE IS
PARKINSONISM, AND THAT USUALLY
DESCRIBES THE MOTOR FEATURES OF
PARKINSON DISEASE.
THOUGH THERE ARE ALSO NON-MOTOR
FEATURES THAT ARE VERY
IMPORTANT.
AND THE OTHER THING THAT WE
MIGHT MENTION IS DEMENTIA WITH
LEWY BODIES OR DLB, WHICH MANY
OF YOU HEARD FROM SONIA
SCHULTZ'S TALK LAST WEEK.
THIS IS -- MANY FEATURES ARE
SIMILAR, ESPECIALLY THE MOTOR
FEATURES ARE SIMILAR TO
PARKINSON DISEASE, BUT THERE'S
MORE SEVERE COGNITIVE DEFICITS
AND MORE RAPID DISEASE
PROGRESSION.
THE OTHER THING THAT WE MIGHT
REFER TO THESE DISORDERS AS LEWY
BODY DISORDERS, OR
SYNUCLEINOPATHIES.
SO LEWY BODIES ARE THESE
INCLUSIONS THAT WE SEE, THEY'RE
INCLUSIONS OF PROTEINS WITHIN
NEURONS, AND ONE OF THE MAIN
COMPONENTS OF THESE LEWY BODIES
ARE A PROTEIN THAT YOU'LL HEAR
ABOUT FROM ANDY CALLED ALPHA
SYNUCLEIN.
IT'S KIND OF AN AMORPHOUS SMALL
NOT VERY STRUCTURED THING THAT
CAN EITHER AGGREGATE INTO
AGGREGATES OR FIBRILS, AND THEY
ARE PRESENT IN THE LEWY BODIES.
YOU CAN SEE THIS IS FROM THE
BRAIN OF ONE OF OUR PATIENTS
ACTUALLY, AND THE LEWY BODY
STAINED POSITIVE FOR ALPHA
SYNUCLEIN.
SO PARKINSON DISEASE IS VERY
COMMON.
IT AFFECTS ABOUT 2% OF THE
POPULATION OVER AGE 65, AND GOES
UP THE OLDER YOU GO.
THERE'S ABOUT 40,000 NEW CASES
PER YEAR HERE IN THE UNITED
STATES.
THEY THINK CLOSE TO A MILLION
PEOPLE IN THE UNITED STATES HAVE
PARKINSON DISEASE, AND I DON'T
THINK THERE'S AN ACCURATE NUMBER
WORLDWIDE, BUT -- AND I'VE SEEN
10 MILLION, MY GUESS IS IT
HIGHER THAN THAT.
THE NUMBER IS GROWING RAPIDLY AS
THE POPULATION AGES, BUT WE'RE
NOT EVEN SURE IF THAT'S THE ONLY
COMPONENT, BECAUSE IT SEEMS TO
BE THAT THERE COULD ALSO AT THE
SAME TIME BE EVOLVING INCREASED
ENVIRONMENTAL AND OTHER
INFLUENCES, BUT IT DOES TEND TO
BE THE FAST ELLEN SIDRAEST GROWG
NEUROLOGIC DISORDER AND IT
PROBABLY HAS CONTRIBUTIONS OF
BOTH JE GENETIC AND ENVIRONMENL
FACTORS BUT OUR FOCUS TODAY IS
ON THE GENES.
EXP
>> GREAT, THANKS, ELLEN.
SO THIS IS GOING TO BE THE
STRUCTURE OF WHAT WE'RE GOING TO
TALK ABOUT TODAY.
HOW FAR HAVE WE COME IN GENETIC
DISCOVERY, I'LL COVER THAT, AND
REALLY FOCUSING ON THESE
GENOME-WIDE EFFORTS, ROOKI LOOKT
THOUSANDS OF PATIENTS MAKING
INFERENCES ABOUT GENETICS FROM
THAT GROUP.
THEN WE'LL COME FROM THE OTHER
ASPECT, WHICH IS FROM ELLEN,
CLUES FROM A SINGLE PATIENT, AND
THIS NOTION OF REALLY ASTUTE
CLINICAL OBSERVATION LEADING TO
A BREAKTHROUGH UNDERSTANDING OF
THE GENETIC BASIS OF DISEASE.
WE'LL THEN PITCH BACK TO ME TO
TALK ABOUT HOW DO WE FIND WHAT'S
LEFT, LIKE WHERE ARE WE HEADING
IN OUR UNDERSTANDING OF THE
GENETIC BASIS OF DISEASE, AND
THEN LASTLY, WE'LL HEAD TOWARDS
THERAPEUTICS, GIVING AN EXAMPLE
OF THERAPEUTIC APPROACHES.
THERE ARE MANY TRIALS, BOTH
SYMPTOMATIC AND ETIOLOGIC-BASED
TRIALS IN PARKINSON'S DISEASE,
BUT THIS WILL SERVE AS ONE
EXAMPLE OF HOW GENETICS LEADS US
TOWARDS A POTENTIAL THERAPEUTIC
AVENUES OF RESEARCH.
SO THIS IS A PRETTY OBVIOUS
SLIDE, I THINK.
THIS COMES TO ANSWER THE
QUESTION WHY DO WE DO GENETICS.
REALLY THE IDEA IS TO UNDERSTAND
BIOLOGY, AND IF WE CAN
UNDERSTAND BIOLOGY OR BIOLOGIES
OF DISEASE, WE CAN THEN FIND
VIABLE THERAPEUTIC TARGETS,
RATIONAL THINGS FOR US TO TRY
AND ATTACK.
SO THAT WE'RE NOT SIMPLY TRYING
TO DEAL WITH SYMPTOMS, WE'RE
REALLY TRYING TO ATTACK THE
UNDERLYING BIOLOGY OF DISEASE
AND I THINK THESE ARE LIKELY TO
BE MANY, MANY TARGETS.
THE OTHER PORTION THAT I THINK
GENETICS MIGHT HELP US IS TO
DISSECT DISEASE.
SO WHAT I MEAN HERE IS,
UNDERSTAND HOW DIFFERENT
MECHANISMS CONTRIBUTE IN AN
INDIVIDUAL, AND ALSO TO PREDICT
COURSE AND OCCURRENCE OF DISEASE
IN AN INDIVIDUAL.
SO THIS IS ALL AROUND THE IDEA
OF IDENTIFYING THE RIGHT
THERAPEUTIC TARGET AND MATCHING
TO THE RIGHT PATIENT AND
DELIVERING THAT THERAPY AT THE
RIGHT TIME, SO RIGHT TARGET,
RIGHT PATIENT, RIGHT TIME.
SO WHERE ARE WE IN THE CONTEXT
OF THE GENETICS OF PARKINSON'S
DISEASE?
SO LIKE MOST NEUROLOGICAL
DISORDERS, WE REALLY FOCUSED ON
MONOGENIC DISEASE IN THE FIRST
INSTANCE.
SO CASES WHERE DISEASE OCCURS
MORE OFTEN THAN ONE WOULD EXPECT
IN A FAMILY, LEADING US TO
SUGGEST THERE IS A SINGLE
MUTATION THAT'S DRIVING DISEASE
IN THAT FAMILY.
THERE ARE AROUND A DOZEN OR SO
GENES THAT CONTAIN MUTATIONS
THAT ARE CAUSATIVE OF
PARKINSON'S DISEASE.
I'VE PUT THEM HERE ON THIS
CIRCULAR GENOME SO YOU'VE GOT
THE AUTO SOMES GOING FROM ONE
THROUGH 22.
THESE HAVE BEEN INCREDIBLY
INFORMATIVE AND INCREDIBLY
INFLINFLUENTIAL IN TERMS OF HOWE
TRY TO MODEL DISEASE AND
UNDERSTAND THE MOLECULAR BIOLOGY
OF DISEASE.
THE VERY FIRST MUTATION
DISCOVERED AS A CAUSE OF
PARKINSON'S DISEASE WAS FOUND
HERE IN 1997.
THIS REALLY CHANGED THE FIELD
ENTIRELY.
SO PARKINSON'S DISEASE WAS OFTEN
THOUGHT OF AS A NON-GENETIC
DISEASE ENTITY, AND EVEN WHEN
THERE WAS SOME EVIDENCE THAT
THERE WAS A GENETIC BASIS TO THE
DISEASE, IT WAS A GENERAL
THOUGHT THAT WHATEVER WAS FOUND
IN FAMILIES JUST WOULDN'T BE
RELEVANT TO THE TYPICAL DISEASE.
SO THIS FINDING REALLY CHANGED
EVERYTHING.
IT SHOWED QUITE SIMPLY THAT
MUTATIONS IN A GENE CALLED ALPHA
SYNUCLEIN ENCODING A PROTEIN
CALLED SYNUCLEIN WHICH ELLEN HAS
ALREADY TALKED ABOUT CAN CAUSE
DISEASE.
SO THE FIRST MUTATIONS FOUND
WERE A53T MUTATION AND THEN AN
E30P MUTATION.
THE FORMER FOUND IN AN ITALIAN
GREEK KINDRED, AGAIN BY
RESEARCHERS HERE, AND
IMMEDIATELY AFTER THAT, IT WAS
SHOWN THAT THE PROTEIN THAT WAS
ENCODED BY THIS GENE, SYNUCLEIN,
WAS A MAJOR COMPONENT OF LEWY
BODIES SO IT LINKED DISEASE IN
THESE REALLY RARE FAMILIES, THAT
LOOKED LIKE THEY HAD A SUPER
RARE PARKINSON'S DISEASE COULD
BE LINKED TO THE PATHOLOGICAL
HALLMARKS OF ALL PARKINSON'S
DISEASE, SHOWING THE GENETIC
BASIS OF RARE DISORDERS CAN BE
INCREDIBLY INFORMATIVE IN TERMS
OF UNDERSTANDING DISEASE AS A
WHOLE.
FOR THE NEXT SIX OR SEVEN YEARS
AFTER THAT, SEVERAL GENES WERE
IDENTIFIED AND THERE WAS A GREAT
DEAL OF WORK ON UNDERSTANDING
WHAT QUALITATIVE CHANGES IN
SYNUCLEIN WOULD DO IN TERMS OF
DISEASE RISK.
OUR GROUP FOUND MUTATIONS THAT
CHANGED QUANTITATIVELY THE
AMOUNT OF SYNUCLEIN THAT WAS
PRODUCED IN 2003, SO ABOUT FIVE
OR SIX YEARS AFTER THE ORIGINAL
SYNUCLEIN MUTATION.
AND DISEASE IN THESE FAMILIES,
THE WATERS MILLER KINDRED, ARE
SIMPLY DRIVEN BY TOO MUCH
SYNUCLEIN.
SO IN THIS ORIGINAL FAMILY, THE
PATIENTS HAVE FOUR COPIES OF
SYNUCLEIN, SO THREE ON ONE
CHROMOSOME, FOUR -- ONE ON THE
OTHER CHROMOSOME, FOUR, AND JUST
HAVING TOO MUCH CAN DRIVE
DISEASE.
IT CAUSES A FAIRLY TYPICAL
PARKINSON'S DISEASE, ALBEIT WITH
PRETTY PROMINENT PATHOLOGY,
PROMINENT DEMENTIA, BUT A FAIRLY
TYPICAL PARKINSON'S DISEASE.
SO QUALITATIVE CHANGES IN
SYNUCLEIN CAN DRIVE DISEASE, AND
JUST INCREASING THE AMOUNT OF
SYNUCLEIN CAN CAUSE DISEASE.
A YEAR OR SO LATER, OUR GROUP
FOUND THE NEXT MUTATION, SOME
MUTATIONS IN A GENE CALLED LRC
IT.
WE CO-DISCOVERED THIS EXACTLY AT
THE SAME TIME AS TOM GASSER'S
GROUP FOUND THIS.
WHAT WAS INTERESTING ABOUT THIS
PARTICULAR MUTATION IS IT WAS
VERY COMMON.
SO AROUND 2% OF ALL NORTHERN
EUROPEAN ANCESTRY CASES CARRIED
THIS MUTATION.
IT GOES UP TO ABOUT 5 OR 6% IF
YOU LOOK AT FAMILIAL CASES, IT
GOES UP TO 20% IF YOU LOOK AT
THE JEWISH POPULATIONS, UP TO
40% IF YOU LOOK IN NORTH AFRICAN
ARAB POPULATIONS.
THIS PARTICULAR MUTATION IS IN
THE KINASE DOMAIN.
IT SEEMS TO INCREASE KINASE
ACTIVITY AND I THINK
IMMEDIATELY, WITHIN A MONTH OR
TWO OF MAKING THE DISCOVERY, IT
BECAME CLEAR THAT KINASE
ACTIVITY WAS A GOOD THERAPEUTIC
TARGET, AND INDEED THIS IS A
THERAPEUTIC TARGET THAT'S BEEN
PURSUED VERY HEAVILY BY MANY
GROUPS AROUND THE WORLD.
THERE'S NOW A LARGE PHASE
3 CLINICAL TRIAL AIMED AT
REDUCING KINASE ACTIVITY, AS
WELL AS OTHER GENETIC-BASED
TRIALS FOR LRRK2.
SEVERAL OTHER MUTATIONS I NOTED
A DOZEN OR SO.
I INCLUDE THREE HERE WHICH WE
ALSO FOUND.
WE HAD A ROLE IN THE DISCOVERY
OF SOME OF THE OTHERS, BUT
THERE'S CONTINUED DISCOVERY.
THERE'S CONTINUED DISCOVERY OF
NEW GENES THAT CONTAIN RARE
MUTATIONS THAT CAUSE DISEASE.
MODERATE RISK VARIANTS, ELLEN IS
GOING TO TALK MORE SIGNIFICANTLY
ABOUT ONE OF THESE, GBA, WHICH
HAS BEEN INCREDIBLY INFORMATIVE
IN OUR UNDERSTANDING OF
SYNUCLEINOPATHIES, NOT JUST
PARKINSON'S DISEASE BUT ALSO
DEMENTIA WITH LEWY BODIES.
THEN MOST RECENTLY, MY LAB HAS
BEEN WORKING ON UNDERSTANDING
THE JE GENETIC BASIS OF COMMON
PARKINSON'S DISEASE, SO THOSE
CASES WHERE THERE ISN'T A
PARTICULARLY STRONG FAMILY
HISTORY, AND WE'VE BEEN DOING
THIS USING GENOME-WIDE
ASSOCIATION STUDY, SO REALLY AT
THE MOST BASIC WHAT THIS IS IS
DOING VERY DENSE GENOTYPING
THROUGHOUT THE GENOME, SO AROUND
A MILLION OR SO SITES IN A VERY
LARGE NUMBER OF INDIVIDUALS.
SO THIS PARTICULAR GENOME-WIDE
ASSOCIATION STUDY WHICH WAS
PUBLISHED ABOUT TWO OR THREE
YEARS AGO INCLUDED SOMEWHERE IN
THE REGION OF 50 TO 60,000
PATIENTS AND ABOUT 1 1/2 MILLION
CONTROLS.
AND YOU SIMPLY LOOK AT THE
DIFFERENCE IN VARIABILITY
BETWEEN THE CASES AND THE
CONTROLS, AND THIS LEADS YOU TO
REGIONS OF THE GENOME THAT
IMPART RISK.
I'M GOING TO COME BACK TO THIS
KIND OF STUDY LATER AND TALK
ABOUT THE KIND OF DIRECTION
WE'RE HEADED IN TO FURTHER
UNDERSTAND THE GENETIC BASIS OF
DISEASE.
BUT AS OF THIS PUBLICATION,
AGAIN, THIS WAS PUBLISHED ABOUT
THREE YEARS AGO, THERE ARE
AROUND 90 OR SO REGIONS IN THE
GENOME THAT CONTAIN RISK
VARIANTS FOR PARKINSON'S
DISEASE.
THERE'S A HUGE AMOUNT LEFT TO BE
FOUND, SO IF WE LOOK AT THE
POPULATIONS THAT WE STARTED
USING GENOME WIDE ASSOCIATION
STUDY, THERE'S 90 RISK LOHSE LOY
REPRESENT ABOUT A THIRD OF THE
INHERITABLE COMPONENT SO WE'VE
ONLY FOUND THE MINORITY OF THE
GENETIC INFLUENCE WE KNOW HAS TO
BE THERE.
BASED ON OTHER COMPLEX TRAITS
LIKE HEIGHT, THERE ARE GOING TO
BE THOUSANDS OF OTHER RISK LOCI
TO BE DISCOVERED.
SO A KEY QUESTION IS, WHY DO WE
LOOK, WHY DO WE CONTINUE TO LOOK
FOR GENETIC VARIABILITY?
PARTICULARLY SOMETHING THAT'S
ASKED IS WHY DO WE LOOK FOR
COMMON GENETIC VARIABILITY WHICH
TENDS TO BE OF LOW EFFECT?
SO THERE ARE A COUPLE OF ANSWERS
TO THIS.
FIRST OF ALL AT EVERY NEW
ASSOCIATION THAT WE FIND, GIVES
US SOME BIOLOGICAL INSIGHT INTO
THE DISEASE PROCESS, RIGHT?
IT'S ANOTHER WINDOW INTO THE
MECHANISM OF THE UNDERLYING
BIOLOGY.
THE SECOND PART IS REALLY BORNE
BY THIS PAPER, WHICH I THINK IS
A BEAUTIFUL PAPER FOR
GENETICISTS, WHICH SHOWS QUITE
SIMPLY THAT IF YOU ARE LOOKING
AT A DRUG TARGET, THE SUCCESS OF
TURNING THAT DRUG TARGET INTO A
THERAPEUTIC IS ABOUT TWICE AS
HIGH IF YOU HAVE GENETIC DATA,
GENETIC EVIDENCE SUPPORTING THAT
TARGET, THAN IF YOU DON'T.
AND IT IS NOT DEPENDENT ON HOW
STRONG THE GENETIC EFFECT IS.
IT'S JUST DEPENDENT ON WHETHER
THAT GENETIC EFFECT IS REAL OR
NOT.
SO THE SIZE OF EFFECT IS
IRRELEVANT WHEN YOU'RE LOOKING
FOR GOOD THERAPEUTIC TARGETS.
SO THE MORE GENES WE CAN FIND
ASSOCIATED WITH DISEASE, THE
MORE INSIGHT WE HAVE INTO
BIOLOGY, THE MORE DIRECT TARGETS
WE HAVE AND THE MORE INDIRECT
TARGETS WE CAN CREATE AS WE
START TO TIE ALL OF THESE GENES
TOGETHER AND THEIR FUNCTIONS
TOGETHER.
I'M ALSO GOING TO SAY PART OF
THE REASON WHY WE NEED TO
CONTINUE LOOKING IS, THIS
PICTURE I'VE SHOWN YOU IS A LIE,
BECAUSE THIS PICTURE I'VE SHOWN
YOU IS GENERALLY THE GENETIC
ARCHITECTURE IN NORTHERN
EUROPEAN ANCESTRY POPULATION.
WE ALMOST KNOW ALMOST NOTHING
THE GENETIC ARCHITECTURE OF
DISEASES IN POPULATIONS OUTSIDE
OF NORTHERN EUROPE.
IF WE THINK OF PARKINSON'S AS A
GLOBAL DISEASE, WHICH IT IS, AND
IF WE BELIEVE THIS CONCEPT THAT
WE NEED TO UNDERSTAND THE BASIS
OF DISEASE IN ORDER TO BE ABLE
TO TREAT IT, WE THEN NEED TO BE
DOING GENETICS IN POP LAITIONS
AROUND THE WORLD.
WE NEED TO UNDERSTAND THE BASIS
OF DISEASE IN IMLOABL
POPULATIONS, KNOW WHAT'S THE
SAME, KNOW WHAT'S DIFFERENT SO
WE CAN TIE TREATMENTS TO
INDIVIDUALS.
WE'RE GOING TO SKIP TO THE NEXT
PRESENTATION NOW.
ELLEN IS GOING TO TAKE US FROM
THIS BROAD VIEW LOOKING AT THE
WHOLE GENOME IN THOUSANDS OF
INDIVIDUALS TO INSIGHTS IN VERY
CAREFULLY CHARACTERIZED
INDIVIDUALS.
>> OKAY.
WELL, IT IS KIND OF FUN TO GO
AFTER ANDY, BECAUSE IT'S SORT OF
LIKE GOING FROM THE TELESCOPE TO
THE MICROSCOPE.
I CAN'T IMAGINE EVER COLLECTING
40,000 SAMPLES OF ANYTHING,
BECAUSE MY CAREER HAS MAINLY
BEEN STUDYING RARE DISEASES.
I LIKE TO TELL PEOPLE THAT I
LIVE IN A VERY SMALL HOUSE, BUT
MY WINDOWS LOOK OUT AT A VERY
LARGE WORLD, AND MY VERY SMALL
HOUSE HAS BEEN A DISEASE CALLED
GAUCHER DISEASE WHICH I'VE SPENT
MY WHOLE CAREER ON, INHERITED
LYSOSOMAL STORAGE DISORDER, AND
FROM THIS WINDOW, I HAVE STARTED
STUDYING PARKINSON DISEASE,
WHICH WAS A DID BIG STRETCH
BECAUSE AS YOU HEARD, I WAS
TRAINED AS A PEDIATRICIAN AND
IT'S PROBABLY ONE DISORDER THAT
I KNEW ABSOLUTELY NOTHING ABOUT.
UNLIKE GAUCHER DISEASE, WE KNOW
IT'S A COMMON COMPLEX DISORDER,
BUT OUR LAB NOW IS REALLY
FOCUSED ON STUDYING THE
CONNECTION BETWEEN THESE TWO IN
A BENCH TO BEDSIDE TRANSLATIONAL
APPROACH WHERE WE COMBINE ALL
DIFFERENT TYPE OF MODALITIES, BE
IT STUDYING THAT POLG, CLINICAL
STUDIES, IMAGING, GENETIC
STUDIES, CELL BUY OCIALTION
PROTEIN STUDIES, SOME OF WHICH
I'M GOING TO TRY TO TALK TO YOU
ABOUT IN THE NEXT FEW MINUTES
AND OTHERS, WE'LL GO FOR ANOTHER
DAY.
BUT I THINK THAT YOU WILL COME
TO APPRECIATE THE RARE GENETIC
DISORDERS CAN PROVIDE A WINDOW
INTO COMMON COMPLEX DISORDERS.
SO GAUCHER DISEASE WAS FIRST
DESCRIBED BY PHILIPE GAUCHER
BACK IN 1882.
HE WAS A MEDICAL STUDENT WHEN HE
MADE THE OBSERVATION, WHICH I
ALWAYS LIKE TO STRESS WHEN I'M
SPEAKING TO STUDENT GROUPS.
I LIKE TO THINK OF IT AS AN NIH
DISORDER BECAUSE IN THE PAST SIX
OR SEVEN DECADES, MOST OF THE
ADVANCES HAVE OCCURRED ACTUALLY
AT THE CLINICAL CENTER, MOSTLY
FROM THE WORK OF ROSCOE BRADY,
WHO IDENTIFIED THE ENZYMATIC
DEFECT IN 1965, AND WAS THE
FIRST TO OFFER TREATMENT FOR
GAUCHER DISEASE IN THE FORM OF A
HIGHLY EFFECTIVE ENZYME
REPLACEMENT.
MY MENTOR, ED GINZ, WAS THE
FIRST TO CLONE THE GENE AND
IDENTIFIED THE FIRST MUTATIONS
AND MAKE THE FIRST ANIMAL MODEL,
AND THE PARKINSON'S STORY
ACTUALLY CAME FROM HERE IN THE
CLINICAL CENTER.
SO GAUCHER DISEASE IS THE
INHERITED DEFICIENCY OF THIS
ENZYME GLUCOCEREBROCYTASE THAT
BREAKS DOWN A LIPID INTO
CERAMIDE AND GLUCOSE, AND WE
OFTEN REFER TO THE ENZYME AS G
CASE AND THE GENE AS GBA1.
SO IT'S AN ENZYME THAT FUNCTIONS
IN THE LYSOSOME LIKE MAYBE 60
OTHER LYSOSOMAL ENZYMES.
IT'S A DISORDER PRIMARILY OF
MACROPHAGES WHERE LYSOSOMES
WITHIN MACROPHAGES BECOME
ENGORGED WITH THIS STORAGE
MATERIAL, GIVING RISE TO THE
CHARACTERISTIC-APPEARING GAUCHER
CELL, WHICH IS SOMETIMES THE
ONLY IMAGE THAT PEOPLE REMEMBER
FROM MEDICAL SCHOOL.
THE GENE IS LOAK LOCATED ON
CHROMOSOME ONE, THERE WAS A
HIGHLY HOMOLOGOUS SEQUENCE
SHARING ABOUT 97% SEQUENCE
HOMOLOGY WITH THE GENE.
AND THIS WAS IMPORTANT WHEN --
FOR LOTS OF REASONS.
TODAY WE KNOW OF 600 DIFFERENT
PATHOGENIC VARIANTS IN THIS GENE
IDENTIFIED IN PATIENTS WITH
GAUCHER DISEASE.
MOST OF THESE 600 ARE RARE.
THERE ARE A FEW THAT ARE COMMON.
THE MOST COMMON VARIANT IN
ASHKENAZI JEWS IS N370S, WHICH
IS ASSOCIATED WITH RELATIVELY
MILD DISEASE.
AND ABOUT 1 IN 12 TO 1 IN 14
ASHKENAZI JEWS CARRY A MUTATION
IN THE GBA GENE.
L44P IS PROP BLI PROBABLY THE MN
MUTATION WORLDWIDE, MORE OFTEN
WHEN IT'S HOMOOLILIC IT'S
ASSOCIATED WITH GAUCHER DISEASE,
BUT THERE'S OTHER MUTATIONS
SPREAD THROUGH ALL THE 11 EXONS
OF THE GENE, AND AS YOU'RE GOING
TO HEAR FROM ANDY A LITTLE BIT,
SOMETIMES IN THE INTRON REGIONS.
SOME PATIENTS ACTUALLY HAVE WHAT
WE CALL RECOMBINANT ALLELES,
WHERE CHUNKS OF THE PSEUDOGENE
GET INTEGRATED INTO THE GENE,
AND THAT'S ANOTHER FORM OF
MUTANT ALLELE.
IT'S ALSO IMPORTANT BECAUSE WHEN
YOU DESIGN PCR PRIMERS OR TRY TO
ALIGN SEQUENCE, YOU HAVE TO BE
AWARE OF THIS HIGHLY HOMOLOGOUS
NEARBY SEQUENCE.
SO GAUCHER DISEASE IS A
MULTIORGAN DISORDER WITH
VARIABLE MANIFESTATIONS.
SOME OF THE KEY FEATURES ARE
SHOWN HERE ON THIS CARTOON.
YOU CAN HAVE GAUCHER CELLS IN
YOUR LIVER, YOU CAN HAVE
ENORMOUS HEPATOSPLENOMEGALY.
FORTUNATELY WE DON'T SEE THIS
ANYMORE HERE BECAUSE PATIENTS
ARE STARTED EARLIER IN
TREATMENT, BUT IN MY FREEZER,
YOU CAN FIND THESE SIX, SEVEN,
EIGHT-KILO SPLEENS THAT WERE
TAKEN OUT PRIOR TO THE ADVENT OF
ENZYME REPLACEMENT THERAPY.
BONE DISEASE IS A COMMON CAUSE
OF MORBIDITY.
YOU CAN HAVE VERY EXQUISITELY
PAINFUL CRISES LIKE SICKLE CELL
PATIENTS HAVE, OR YOU CAN HAVE
DEFORMITIES WITH NOT TOO MANY
SYMPTOMS.
THE CLASSIC RADIOGRAPHIC FIND
SOMETHING WHAT THEY CALL THERLIN
MEYER FLASK DEFORMITY OF THE
DISTAL FEMUR, AND WE SEE THAT IN
MOST PATIENTS EVEN THOUGH
THEY'RE NOT AWARE OF IT.
AND IN SOME PATIENT, THE RARE
ONES, THERE CAN BE BRAIN
INVOLVEMENT.
THOUGH WE DON'T SIGO HSIEH CELLS
SEE GAUCHERCELLS IN THE BRAIN, Y
THEY'RE SEEN PERIVASCULARLY.
SO HOW DO WE EXPLAIN THIS VAST
DISORDER?
WHEN I FIRST CAME TO NIH, THE
GENE HAD JUST BEEN CLONED AND I
THOUGHT VERY NAIVELY THAT I
WOULD IDENTIFY MUTATIONS,
PHENOTYPE PEOPLE, PUT IT ALL
TOGETHER AND BE ABLE TO EXPLAIN
EVERYTHING AND 30 YEARS LATER,
NO WAY, BUT IN ANY CASE, THE
DISEASE HAS BEEN CLASSICALLY
GROUPED INTO THREE TYPES.
TYPE 1 BY DEFINITION IS NON
NON-NEURONOPA THICK, THE MOST
COMMON IN ASHKENAZI JEWS AND
ACTUALLY THE MOST COMMON FORM IN
THE UNITED STATES.
TYPE 2 IS A HORRIBLE DEVASTATING
NEURODEGENERATIVE DISORDER THAT
BEGINS IN INFANCY.
AND WE REALLY HAVE NO EFFECTIVE
TREATMENTS FOR.
AND TYPE 3, BY DEFINITION, IS
ANY PATIENT THAT SURVIVES THE
FIRST YEARS OF LIFE BUT HAS ANY
FORM OF NEUROLOGIC INVOLVEMENT,
OFTEN JUST THE SLOWING OF THE SI
KA TICK EYE MOVEMENTS.
BUT THE MORE I'VE SEEN PATIENTS
HERE OVER THE YEARS AND I'VE
BEEN DOING THIS NOW MORE THAN
THREE DECADES, I'VE BEGUN TO SEE
THIS AS A SPECTRUM RANGING FROM
ASYMPTOMATIC OCTO JE NARIANS
THAT ARE ONLY DIAGNOSED BECAUSE
A FAMILY MEMBER OR THERE'S SOME
SCREENING GOING ON, EVEN RIGHT
NOW FROM PARKINSON CLINICS, ALL
THE WAY DOWN TO BABIES THAT DIE
IN UTERO WITH A BIG SPECTRUM IN
BETWEEN, AND OUR PARKINSON'S
STORY FITS SOMEWHERE WITHIN THIS
SPECTRUM.
SO FOR ME, THE STORY BEGAN IN MY
CLINIC BACK IN 1996 WITH A
SINGLE PATIENT I'M GOING TO TRY
AND SHOW YOU, EVEN THOUGH IT'S A
GRAINY OLD VIDEO.
LET'S SEE IF IT WORKS.
IT DID.
SO MARJORIE WAS DIAGNOSED WITH
GAUCHER DISEASE AT AGE 19, HER
TREMOR BEGAN AT AGE 42.
SHE STARTED HAVING PROGRESSIVE
RIGIDITY.
I THINK YOU SEE HER HERE AT
ABOUT AGE 48.
SHE HAS TROUBLE GETTING UP FROM
A CHAIR.
DIFFICULTY INITIATING MOVEMENTS.
SHE HAS THAT MASK FAY MASK F F.
SHE DEVELOPED UNFORTUNATELY
PROGRESSIVE DEMENTIA.
SHE DIED, WE SAW HER SEVERAL
TIMES, SHE DIED AT AGE 54.
SHE WAS FROM NEW HAMPSHIRE AND
ACTUALLY AGREED TO HAVE HER BODY
SHIPPED HERE SO WE COULD DO THE
NEUROPATHOLOGY HERE.
SO AT THE TIME, I WONDERED WHAT
COULD THIS JUST BE A COINCIDENCE
JUST BECAUSE YOU HAVE A RARE
DISEASE DOESN'T MEAN YOU'RE
IMMUNE FROM COMMON DISEASES, OF
COURSE.
BUT WHEN I STARTED TALKING TO
OTHER PEOPLE AT MEETINGS AND
GOING THROUGH THE OLD
LITERATURE, ALMOST EVERY GAUCHER
CLINIC HAD A FEW PATIENTS THAT
HAD DEVELOPED PARKINSON DISEASE.
WE TRIED TO GET THEM TO SEE WHAT
THEY SHARED AND IN 2003, WE
PUBLISHED A SERIES OF 17
PATIENTS THAT HAD GAUCHER AND
PARKINSON DISEASE.
AND THE STORY SORT OF MIGHT HAVE
STOPPED THERE BUT THERE WERE TWO
OTHER THINGS.
WE STARTED REALIZING THAT WHEN
WE INTERVIEWED FAMILIES
CAREFULLY, WE TALLIED THE 12 OUT
OF 45 CONSECUTIVE PATIENTS HAD
RELATIVES THAT HAD PARKINSON
DISEASE, OFTEN A PARENT OR A
GRANDPARENT WHO WAS AN OBLIGATE
CARRIER, AND THEN WE ALSO FOUND
OUT THERE WAS SIMILAR THINGS
BEING SEEN IN OTHER GAUCHER
CENTERS, INCLUDING THE LARGE ONE
IN JERUSALEM.
SO THIS WAS THE FIRST EVIDENCE
THAT HETEROZYGOTES WERE ALSO AT
INCREASED RISK FOR PARKINSON
DISEASE.
AND THEN THE PLOT THICKENS, AS
DR. KASTNER WOULD SAY.
I GOT A CALL FROM CATHY, HOWARD
HUGHES MEDICAL STUDENT IN OUR
LAB IN THE 80s OR 90s, AND
SHE SAID SHE WAS NOW CHIEF
NEUROPATHOLOGY FELLOW AT MASS
GENERAL AND SHE WAS DOING AN
AUTOPSY ON A CASE WITH
PARKINSON'S DISEASE AND SHE READ
THE CHART.
GOOD PATHOLOGIST.
AND SAW THAT THE GUY HAD
GAUCHER, DID A GOOGLE, FOUND OUR
PAPERS, AND ASKED ME IF I WANTED
ANYTHING FROM THE AUTOPSY, WHICH
WAS REALLY GENERAL CUSS.
GENEROUS.
BUT I SAID YES BUT I DON'T HAVE
ANY IDIOPATHIC PARKINSON'S
DISEASE, CAN YOU SEND ME A FEW.
SO SHE PACKAGED ME UP A PACKAGE
ON DRY ICE WITH THREE LITTLE
SNPPETS OF BRAIN, AND WHEN IT
GOT HERE, I COULDN'T RECOGNIZE
THE LABELS, AS OFTEN HAPPENS ON
DRY ICE AND MINUS 80 FREEZERS.
SO I HAD THE PEOPLE IN MY LAB
CHIP OFF A PIECE AND DO ENZYME
ACTIVITY.
AND LO AND BEHOLD, ONE OF THE
SAMPLES WAS EXTREMELY LOW AND
THAT WAS THE THE ONE THAT I
THINK SHE WAS REFERRING, BUT THE
OTHER TWO WERE ALSO LOWER THAN
WE EXPECTED.
SO WE SCRATCHED OUR HEAD AND
SAID WHAT'S GOING ON HERE, AND
WE SAID WELL, GO CHIP OFF
ANOTHER PIECE AND WE'LL SEQUENCE
THE DNA.
ONE WAS AN N370 HOMOZYGOTE BUT
THE OTHER TWO BOTH CARRIED -- WE
CONTACTED CATHY AND ASKED HER TO
SEND US MORE BRAINS AND I WENT
TO MULTIPLE BRAIN BANKS WITHIN
THE UNITED STATES AND WITHIN A
FEW MONTHS, WE COLLECTED 57
CASES, AND 12 HAD VARIANTS IN
THE GBA GENE.
THAT WAS LIKE REALLY HARD TO GET
ACCEPTED IN THE COMMUNITY FIRST
OF ALL, FOR SOME REASON GWAS AT
THAT POINT HADN'T PICKED UP GBA.
SO THEY THOUGHT MAYBE THERE WAS
SOME BIAS, MAYBE THEY WERE ALL
ASHKENAZI DONORS, SO WE WENT
BACK TO KATHY AND THE OTHER
BRAIN BANKS AND SEQUENCED GBA
AND 44 CONTROLS AND DIDN'T FIND
ANY VARIANTS.
SO SENT THIS OUT TO MULTIPLE
JOURNALS, EVENTUALLY WE GOT IT
PUBLISHED IN A GENETICS JOURNAL,
AND THEN OTHER GROUPS STARTED
LOOKING IN THEIR COHORT, AND
AGAIN, THEY KEPT ON FINDING THAT
THERE WERE MORE GBA VARIANTS
THAN YOU'D EXPECT, BUT STILL IT
DIDN'T REALLY GAIN MOMENTUM
UNTIL JOHN HARDIG CHALLENGED US
TO PUT TOGETHER AN INTERNATIONAL
STUDY OF GBA MUTATIONS IN
PARKINSON DISEASE.
AND AT THAT POINT, WE ASSEMBLED
16 CENTERS, FOUR CONTINENTS, WE
HAD ABOUT 5,000 PATIENTS WITH
PARKINSON DISEASE AND 5,000 WITH
CONTROLS.
WE SENT A PANEL TO SEE WHICH
MUTATIONS EACH LAB COULD PICK
UP.
THEY COULDN'T PICK THEM UP A UP
BUT AT LEAST THE TWO COMMON ONES
SEEMED FAIR ENOUGH, SO JUST
BASED ON THOSE TWO COMMON
MUTATION, WE FOUND PATIENTS WITH
PARKINSON'S DISEASE WERE FIVE
TIMES MORE LIKELY TO HAVE A GBA
VARIANT.
ALREADY FROM THIS EARLY PAPER,
WE FOUND THAT THE GBA CARRIERS
TENDED TO HAVE EARLIER PARKINSON
ONSET AND MORE COGNITIVE
DEFICITS.
ACTUALLY A FEW YEARS LATER, WE
WENT BACK TO THE SAME CENTERS,
AND TRIED TO DO REPLICATE TYPE
OF STUDY DEMENTIA WITH LEWY
BODIES, RARE DISORDER, WE ONLY
HAVE 721 CASES, BUT ACTUALLY THE
GLB, THE DLB, THE ODDS RATIO WAN
HIGHER, SO WHY IS IT IMPORTANT?
WELL, AS ANDY MENTIONED, FINDING
A GENE CAN FOCUS YOUR ATTENTION
AND SOMETIMES TO A NEW PATHWAY,
COMPARED TO A LOT OF THE OTHER
GENES AT THE TIME, WE KNEW A LOT
ABOUT GBA1 AND IT'S ROLE IN THE
LYSOSOME, AND IN FACT,
SUBSEQUENTLY, WE'RE BECOMING
AWARE THAT MANY OF THE GENES
THAT RUTH BADER GINSBURG
THAT ARE BEING IDENTIFIED FALL
INTO LYSOSOMAL PATHWAYS.
TODAY IF YOU GOOGLE OR DO A
PUBMED ON GBA YOU'LL FIND 10
TIMES MORE PAPERS ABOUT
PARKINSON'S DISEASE THAN YOU
WILL ABOUT GAUCHER DISEASE.
AND MANY DIFFERENT PARKINSON
GROUPS ARE FUNDING WORK ON THE
GLUCOVEE ROW SIDASE GENE
INCLUDING MICHAEL J. FOX AND THE
BIG INITIATIVE AND MOST BIG
PHARMA THAT ARE INTERESTED IN
NEURODEGENERATION NOW HAVE GBA
PROGRAMS.
WHICH IS GREAT FOR PATIENTS WITH
GAUCHER DISEASE BECAUSE THEY
NEVER HAD THAT MUCH ATTENTION.
SO FOR SOME TIME NOW WE'VE BEEN
DOING A PROSPECTIVE STUDY AT THE
NIH TO SEE IF WE COULD FIND
EARLY CLINICAL FEATURES THAT
MIGHT BE PREDICTIVE OF
PARKINSON'S, A MOVEMENT DISORDER
PERSON IN MY GROUP HAS BEEN
DOING THESE EVALUATIONS.
WE RECRUIT PATIENTS THAT HAVE
GAUCHER DISEASE AND PARKINSON
DISEASE AND ALSO GAUCHER
CARRIERS WITH PARKINSON DISEASE.
BUT AT THE SAME TIME, WE'RE
RECRUITING PATIENTS WITH GAUCHER
DISEASE AND GAUCHER CARRIERS WHO
DON'T IS PARKINSON DISEASE, BUT
THEY HAVE A STRONG FAMILY
HISTORY IN A PARENT OR SIBLING.
THEY COME AND UNDERGO A PRETTY
UNIFORM CLINICAL SET OF STUDIES
THAT HAS BEEN GOING ON FOR OVER
15 YEARS.
THEY HAVE A PHYSICAL EXAM,
NEUROLOGIC EXAM, NEUROCOGNITIVE
EVALUATIONS.
WE TEST THEIR ABILITY TO SMELL,
WE SCREEN FOR OTHER NON-MOTOR
FEATURES, AND THEN FOR A WHILE,
WE'VE BEEN DOING DIFFERENT
IMAGING STUDIES INCLUDING MRI,
PET SCANS, AND TRANSCRANIAL SEW
SONOGRAPHY.
SO TO SUMMARIZE LIKE 15 YEARS OF
STUDY ON ONE SLIDE, GENERALLY WE
FIND THAT OUR PATIENTS THAT HAVE
GAUCHER DISEASE AND PARKINSON
DISEASE HAVE CLINICAL AND
POTASSIUM LOGIC FINDINGS THAT
PATHOLOGIC FINDINGS THAT REALLY
RESEMBLE IDIOPATHIC PARKINSON
DISEASE.
SOME DO HAVE CLINICAL AND
PATHOLOGIC FEATURES THAT ARE
MORE SIMILAR TO DEMENTIA WITH
LEWY BODIES.
THEY SEEM TO HAVE SIMILAR
TREATMENT RESPONSES TO L-DOPA.
THE AGE OF PD ONSET TENDS TO BE
YOUNGER BY ABOUT TWO TO SIX
YEARS WITH A MEAN OF ABOUT 47.
THEY ARE MORE LIKELY TO HAVE A
POSITIVE FAMILY HISTORY,
NON-MOTOR SYMPTOMS ARE COMMON,
ESPECIALLY OLFACTION SEEMS TO BE
IMPACTED.
PROGRESSION MAY BE A LITTLE
FASTER, AND THERE MAY BE MORE
COGNITIVE DYSFUNCTION, BUT I
ALWAYS LIKE TO EMPHASIZE NOT
ALWAYS, ESPECIALLY WHEN I'M
COUNSELING PATIENTS.
HOWEVER, IN OUR RISK COHORT, NOW
WE'VE SEEN ABOUT 113 PATIENTS,
SOME OF WHOM HAVE BEEN FOLLOWED
FOR UP TO PIRN TO 13 TO 15 YEARE
ONLY HAD ONE CONVERT, WHICH HAS
REALLY BEEN FRUSTRATING FOR US
BECAUSE WE'VE PUT IN A LOT OF
EFFORT TO TRY TO PREDICT THE
CONVERTERS, BUT IT'S GREAT NEWS
FOR OUR PATIENTS.
SO CLEARLY NOT ALL PATIENTS WITH
MUTATIONS ARE ON A PARKINSON
TRAJECTORY.
THIS IS JUST SUMMARIZING SOME OF
THE PATIENTS WITH GAUCHER AND
PARKINSON DISEASE THAT WE'VE
SEEN.
AGAIN SOME OF THEM HAVE PRETTY
CLASSIC PARKINSON COURSE THOUGH
OTHERS HAVE THE MORE AGGRESSIVE
EARLY ONSET FORM.
THE N370S MUTATION, WHICH IS
CONSIDERED NON-NEUROLOGIC IN
GAUCHER DISEASE IS IN THE UNITED
STATES THE MOST COMMON MUTATION.
THERE ARE FEW VARIANTS THAT ARE
SEEN I -- IN THE GENE THAT ARE
SEEN IN PARKINSON DISEASE THAT
DON'T CAUSE GAUCHER DISEASE THAT
MAY BE MORE COMMON, BUT MOST OF
OUR PATIENTS RESPOND WELL TO
L-DOPA OLFACTION AND COGNITION
ARE COMMONLY IMPAIRED.
THIS IS WHAT WE SEE, THE FIRST
WOMAN ON OUR LEFT WAS DIAGNOSED
IN HER 40s BUT HAD A 28-YEAR
COURSE AND ONLY HAD LATE
COGNITIVE FINDINGS.
THE GENTLEMAN IN THE MIDDLE CAME
TO US NEWLY DIAGNOSED IN HIS
LATE '50S, ALREADY CONFUSED WITH
BOOKKEEPER, COULDN'T KEEP THE
NUMBERS STRAIGHT, DIED A FEW
YEARS LATER WITH PROGRESSIVE
DEMENTIA.
AND THE GENTLEMAN ON YOUR FAR
LEFT IS ACTUALLY AN ISRAELI
PROFESSOR SEEN HERE SEVERAL
TIMES.
HE KNEW SEVEN LANGUAGES.
HE WOULD SPEAK TO THE X-RAY TECH
ON THE PET MACHINE IN CHINESE,
AND DIED FROM UNRELATED CAUSES
WITH NORMAL COGNITION.
SO YOU KNOW, EVEN THOUGH THERE'S
TRENDS, YOU HAVE TO APPRECIATE
THAT THERE IS THIS RANGE.
ONE APPROACH THAT WE'VE HAD IS
WE'VE BEEN FOCUSING A LOT ON
SIBLINGS, AND WE'VE COLLECTED
NOW 10 SIBLINGS -- WHERE BOTH
SIBLINGS HAVE GAUCHER DISEASE
BUT ONLY ONE DEVELOPED PARKINSON
DISEASE.
WE'VE SEEN THESE SIBLINGS NOW,
SOME OF THEM UP TO SEVEN OR
EIGHT TIMES OVER THE LAST 16
YEARS, AND EACH TIME THEY GO
THROUGH THE WHOLE BATTERY OF
EVALUATIONS.
SO FAR WE HAVEN'T SEEN ANY
INDICATIONS OF PARKINSON DISEASE
OR CHANGES IN PET SCAN IN THE
NON-PARKINSON DISEASE SIBLING,
BUT WE COLLECT ALL KINDS OF
SAMPLES INCLUDING DNA, RNA,
FIBROBLASTS, ET CETERA, BECAUSE
I THINK THAT THESE KIND OF
DISCORDANT SIBLINGS WILL BE
IMPORTANT AS WE TRY TO EVALUATE
WHAT PROTECTS OR WHAT CONFERS
MORE RISK.
BECAUSE REMEMBER, MOST GAUCHER
PATIENTS AND CARRIERS NEVER
DEVELOP PARKINSON DISEASE.
IT JUST A RISK FACTOR.
BUT OUR CHALLENGE IS TO IDENTIFY
THE OTHER FACTORS OR GENES THAT
EITHER INCREASE OR DECREASE
ONE'S RISK FOR PARKINSON
DISEASE, BUT I THINK WE'RE
FINALLY AT THE POINT WHERE WE
CAN USE SOME GENOMIC APPROACHES
ALSO.
AS YOU HEARD FROM ANDY, THERE'S
ALL KINDS OF NEW TECHNOLOGICAL
ADVANCES THAT ARE ENABLING US SO
BETTER UNRAVEL ALL THE DIFFERENT
FACTORS THAT CONTRIBUTE TO OUR
COMPLEX INDIVIDUAL TAPESTRIES,
AND IN THE CASE OF PARKINSON
DISEASE, WE CAN USE STRATEGIES
LIKE LOOKING AT GENOMES,
EPIGENOMES, TRANSCRIPTOMES, TO
SEE SOME DIFFERENCES.
WE CAN LOOK AT PATIENTS WITH
PARKINSON'S DISEASE WITHOUT GBA
MUTATIONS AND I KNOW ANDY HAS
DONE SOME OF THAT WORK ALREADY.
IT CAN COME FROM ALL THESE BIG
PARKINSON CONSORTIUMS.
AND OTHER APPROACH IS TO LOOK AT
PATIENTS WITH GAUCHER DISEASE
WITH AND WITHOUT PARKINSON
DISEASE AND WE'VE BEEN TRYING
THAT TOO.
UNFORTUNATELY THE NUMBERS ARE
NOT WHAT YOU USUALLY NEED FOR
THESE KIND OF STUDIES.
SO COLLABORATION IS REALLY
ESSENTIAL IN ORDER TO REACH
POWER THAT WILL BE USEFUL.
SO I'M NOT GOING TO SPEND A LOT
OF TIME ON MECHANISM.
THERE'S BEEN LOTS OF THEORIES
AND I JUST DON'T FEEL THAT ANY
OF THEM HAVE BEEN ADEQUATELY
SUBSTANTIATED.
WE DO KNOW THAT THERE IS SOME
KIND OF LINK BETWEEN ALPHA
SYNUCLEIN AND GLUCOCEREBROSIDASE
BUT IT'S AN INVERSE
RELATIONSHIP, AND IN FACT,
PATIENTS WITH JUST PARKINSON
DISEASE WHO DON'T HAVE GBA
MUTATIONS TEND TO HAVE LESS
GLUCOCEREBROSIDASE.
SO I DON'T KNOW -- AS I KEEP ON
TELLING YOU, NOT ALL PEOPLE THAT
HAVE DEFICIENT
GLUCOCEREBROSIDASE GET PARKINSON
DISEASE BUT MAYBE THERE'S SOME
COMPONENTS WITH AGING WHERE WE
TEND TO HAVE MORE SYNUCLEIN, WE
HAVE LESS GOOD LYSOSOMAL
FUNCTION AND APPARENTLY
GLUCOCEREBROSIDE LEVELS COME
DOWN SO MAYBE THERE'S SOMETHING
IN AGING THAT CAN SHIFT THE
BALANCE, OR MAYBE
GLUCOCEREBROSIDASE JUST HAS
ANOTHER ROLE THAT WE'VE STILL
NOT ELUCIDATED.
SO MY TAKE-HOME MESSAGE IS FOR
THIS SHORT PART ARE THAT
MUTATIONS IN GBA ARE A RISK
FACTOR EVEN IN CARRIERS.
MOST PATIENTS AND CARRIERS NEVER
DEVELOP PARKINSON DISEASE.
BUT I TRULY BELIEVE THAT
LEARNING MORE ABOUT THIS
CONNECTION WILL IMPROVE OUR
UNDERSTANDING REALLY OF BOTH
DISEASES AND WILL HELP INFORM
DRUG DEVELOPMENT, WHICH I'LL
TALK ABOUT LATER.
>> GREAT.
THANKS, ELLEN.
OKAY.
SO WE'VE TALKED A BILL LITTLE
ABOUT HOW FAR WE'VE COME IN
GENETIC DISCOVERY, AND HOPEFULLY
WE'VE MADE A PERSUASIVE ARGUMENT
THAT UNDERSTANDING THE GENETIC
BASIS OF DISEASES IS KIND OF
IMPORTANT IF WE WANT TO COME UP
WITHWITH RATIONAL TARGETS FOR
THERAPEUTIC DEVELOPMENT AND
MATCH THOSE THERAPIES TO
PATIENTS.
SO I GUESS THE CRITICAL QUESTION
IS HOW DO WE CONTINUE TO
DISCOVER GENETIC DRIVERS OF
DISEASE?
SO I'M GOING TO TALK ABOUT ONE
MECHANISM THAT WE'VE BEEN USING
TO TRY AND DO THIS, AND TO TRY
AND DO THIS ON A GLOBAL SCALE SO
THIS IS A PROGRAM CALLED THE
GLOBAL PARKINSON'S GENETICS
PROGRAM, WHICH I LEAD ALONG WITH
CORNELIS PLAUWENDRAAT BUT REALLY
INCLUDES THOUSANDS OF PEOPLE.
SO THE MISSION OF GP2 IS A VERY
SIMPLE ONE, TO DRAMATICALLY
EXPAND OUR UNDERSTANDING OF THE
GENETIC BASIS OF DISEASE, BUT TO
DO THAT IN A GLOBAL CONTEXT.
AGAIN WITH THIS NOTION OF IF
WE'RE GOING TO TREAT A GLOBAL
DISEASE, WE NEED TO UNDERSTAND
THE BASIS OF THAT DISEASE ACROSS
WORLDWIDE POPULATIONS.
SO THE OVERARCHING THEME IS
GLOBAL DISEASE.
WE KIND OF HAVE THESE SEPARATE
AREAS OF COMPLEX DISEASE AND
MONOGENIC DISEASE BUT THEY'RE
REALLY A CONTINUUM.
THEY'RE JUST SEPARATED BECAUSE
IT MAKES WORK GROUPS A BIT
EASIER.
ESSENTIALLY WHAT WE'LL BE DOING
IS GENERATING GENETIC
INFORMATION AROUND 200,000
INDIVIDUALS, SO DENSE
GENOME-WIDE GENOTYPING ON AROUND
200,000, AND A SHIFT TO WHOLE
GENOME SEQUENCING ON A LARGE
PROPORTION OF THOSE.
THERE ARE SOME REALLY KEY
STRUCTURAL PRIORITIES FOR GP2.
I THINK THAT TYPICALLY WHAT'S
HAPPENED IS, WHEN WE'VE TRIED TO
LOOK AT DISEASE ACROSS WORLDWIDE
POPULATIONS, WHAT'S HAPPENED IS
REALLY WELL-FUNDED LABS HAVE
GONE INTO THOSE POPULATIONS,
WORKED WITH LOCAL INVESTIGATORS,
COLLECTED SAMPLES, BROUGHT THEM
BACK, ANALYZED THEM, PUBLISHED
THEM, THE END.
WHAT WE'RE TRYING TO DO HERE IN
GB2 IS SLIGHTLY DIFFERENT IN
THAT WE'RE TRYING TO ENABLE
RESEARCH IN THE VERY POPULATIONS
WHERE THOSE SAMPLES ARE
COLLECTED.
SO THERE'S A REALLY LARGE FOCUS
ON DEMOCRATIZATION OF THE
RESEARCH PROCESS, SO MAKING DATA
AVAILABLE, USABLE AND ACTION
ACTIONABLE.
BY RESEARCHERS AROUND THE WORLD,
COLLABORATING, COOPERATING,
SHARING DATA IN A SAFE,
RESPONSIBLE WAY, BEING EXTREMELY
TRANSPARENT IN HOW WE DO OUR
RESEARCH AND MAKING SURE THAT
THE RESEARCHERS ARE REPRESENTED
FROM THE POPULATIONS THAT
PATIENTS ARE COLLECTED.
SO REALLY THERE ARE FOUR THEMES
THAT ARE PULLED TOGETHER, THINGS
LIKE BUILDING LOCAL
INFRASTRUCTURE, IMPROVING
TRAINING AND SKILLSETS IN LOCAL
INVESTIGATORS, FACILITATING
COLLABORATION AND NETWORK
BUILDING WITH THOSE
INVESTIGATORS, GROWING THE NEXT
GENERATION OF LEADERS, SO
FINDING YOUNG INVESTIGATORS, NEW
INVESTIGATORS TO PD RESEARCH AND
GIVING THEM OPPORTUNITIES FOR
GROWTH AND PLACES TO DO THEIR
WORK.
APPLYING TRANSFORMATIVE GENETIC
METHODS.
SO I TALKED A LITTLE ABOUT
GENOME WIDE ASSOCIATION, WHOLE
GENOME GENOTYPING, LONG READ
SEQUENCING, THINGS LIKE THAT,
REALLY TRANSFORMATIVE METHODS.
AND THEN ACCELERATING DISCOVERY
BY DEMOCRATIZING DATA.
WHAT I MEAN HERE IS, I THINK IN
THE GENETICS COMMUNITY, WE'VE
BEEN PRETTY GOOD AT SHARING DATA
FOR A FAIRLY LONG TIME.
BUT YOU NEED RESOURCES AND
SKILLS TO BE ABLE TO DO ANYTHING
USEFUL WITH THAT DATA.
SO AS PART OF GP2, WE'VE CREATED
AN INFRASTRUCTURE THAT NOT ONLY
MAKES THE DATA AVAILABLE,
PROVIDES COMPUTE INFRASTRUCTURE,
SO ALL YOU NEED IS A CONNECTION,
AN INTERNET CONNECTION TO THE
DATA, AND TRAINING IN ORDER TO
BE ABLE TO ACTUALLY DO THE
ANALYSES THAT YOU NEED TO DO.
AND I'LL MENTION A COUPLE THINGS
ABOUT THAT.
SO WHAT THIS PRODUCES IS REALLY
A SELF-PROPAGATING DISCOVERY
ENGINE.
RESEARCHERS SCATTERED AROUND THE
WORLD, MAKING AN ENABLING
TRANSFORMATIVE DISCOVERIES.
IN TERMS OF TRAINING, SO WE HAVE
CREATED A SERIES OF VIDEOS,
ABOUT 80 COURSES NOW, WHICH
ALLOW YOU TO LEARN HOW TO DO
GENETIC ANALYSIS.
THE MOST BASIC ONE IS GENETICS
FOR THE P.I., WHICH I'M IN, AND
SHOWS YOU HOW IF YOU DON'T KNOW
HOW TO DO ANY CODING, YOU CAN GO
FROM ZERO TO 60 FAIRLY QUICKLY,
AND THEN THROUGH TO VERY
COMPREHENSIVE GENETIC ANALYSIS
METHODS.
THESE 80 COURSES ARE AVAILABLE
FOR FREE IN MORE THAN 100
DIFFERENT LANGUAGES, WE HAVE
ALMOST A THOUSAND USERS AROUND
THE WORLD NOW, INCLUDING A THIRD
OF WHICH ARE FROM LOW AND MEDIUM
INCOME COUNTRIES.
SO AN INVESTIGATOR CAN COME
ALONG FROM ANYWHERE IN THE
WORLD, ACCESS THE DATA, ONCE
THEIR DATA ACCESS HAS BEEN
APPROVED, THEY HAVE THE
COMPUTATIONAL METHODS AND POWER
AVAILABLE IN THE CLOUD, ALL OF
THE COMPUTATION IS ATTACHED, AND
THEY CAN LEARN HOW TO DO THESE
ANALYSIS, SO YOU CAN DO
EXTREMELY COMPLEX ANALYSES ON
LARGE DATASETS.
WE ALSO BUILD GLOBAL RESEARCH
CAPACITY BY BRINGING PEOPLE
TOGETHER, SO WE'VE HAD SEVERAL
MEETINGS, TWO IN-PERSON ANNUAL
MEETINGS FOR THE ENTIRE
CONSORTIUM, SO LAST YEAR'S
MEETING HAD ALMOST 300 ATTENDEES
FROM 60 DIFFERENT COUNTRIES.
THAT WAS HELD IN COPENHAGEN.
I'VE JUST COME BACK FROM A
REGIONAL MEETING FOR SOUTH AND
CENTRAL AMERICA IN CARTAGENA.
WE HAD MEETINGS IN KUALA LUMPUR,
AND AFRICA, FIND RESEARCHERS,
WORK WITH THEM TO MAKE SURE THEY
HAVE THEIR NEEDS MET TO DO THIS
RESEARCH.
WE'VE ALSO HELPED TO BUILD SOME
LOCAL CAPACITY LIKE BUILDING A
LOCAL BIOBANK, TRAINING PEOPLE
HOW TO DO TRAINING WORKSHOPS SO
WE HAVE THIS KIND OF
SELF-FULFILLING GRIP OF
INVESTIGATORS WHO CONTINUE TO
TRAIN OTHER INVESTIGATORS IN
DATA ANALYSIS AND CLINICAL
RESEARCH.
WE ALSO HAVE PH.D. AND MASTERS
STUDENTS SCATTERED AROUND THE
WORLD.
YOU CAN SEE HERE THE LATEST
SWATH WERE FIVE ADDITIONAL PH.D.
STUDENTS, SO AGAIN, TRAINING
INVESTIGATORS FROM THE VERY
SITES WHERE WE'RE GETTING
SAMPLES FROM WITH THIS NOTION
THAT WE HAVE REALLY INTERESTED,
DRIVEN SCIENTISTS WHO CAN PUSH
THE NEEDLE FORWARD.
SO WHERE ARE WE?
THERE ARE AROUND 170,000 SAMPLES
IN OUR PIPELINE, 45,000 HAVE
BEEN GENOTYPED AND ARE AVAILABLE
NOW.
YOU CAN GO TO AMP PD, THE NIH'S
PUBLIC-PRIVATE PARTNERSHIP AND
ACCESS GENETIC DATA ON 45,000
SAMPLES NOW.
IT'S A VERY SHORT APPLICATION
PROCESS.
THEY JUST MAKE SURE YOU'RE A
BONA FIDE RESEARCHER AND THEN
YOU HAVE ACCESS TO THE DATA.
THE COMPUTE RESOURCES, ALL OF
THE TRAINING MATERIALS AND YOU
CAN DO WHATEVER ANALYSIS YOU'D
LIKE TO DO.
YOU CAN SEE WE'RE FAIRLY
SCATTERED AROUND THE WORLD, SO
THERE'S STILL LOTS OF PLACES FOR
US TO GO AND EXPAND, BUT WE'RE
WELL ON OUR WAY TO COLLECTING
THE 200,000 SAMPLES WE SAID WE
WOULD.
WE HAVE THROUGH 2029 TO FINISH
THIS.
SO WHAT DOES THIS PRODUCE?
WE'RE STILL FAIRLY EARLY IN THIS
PROCESS, SO I'M GOING TO GIVE
YOU TWO EXAMPLES OF WHAT THIS
WOULD -- WHAT KINDS OF RESEARCH
THIS WILL PRODUCE.
BUT THESE ARE FAIRLY
PRELIMINARY.
PRELIMINARY BUT PRETTY COOL.
SO MULTI-ANCESTRY GENOME WIDE
ASSOCIATION STUDY.
THIS WAS JUST PUBLISHED IN
GENETICS A FEW WEEKS AGO.
HERE THE POWER IS NOT
NECESSARILY IN NUMBERS BUT IN
COMPARING GENETIC ASSOCIATION
ACROSS DIFFERENT POPULATIONS.
SO FOUR DIFFERENT POPULATIONS,
EUROPEAN, EAST ASIAN, LATINO,
WITH FAIRLY MODEST SAMPLES FROM
EAST ASIA, LATIN AMERICAN
COUNTRIES AND AFRICA.
BUT REMARKABLE DISCOVERIES, EVEN
ADDING ONLY A SMALL NUMBER OF
SAMPLES FROM DIFFERENT
POPULATIONS HAS GIVEN US ANOTHER
DOZEN OR SO RISK LOCI, INCLUDING
THINGS THAT ARE DIFFERENT IN
DIFFERENT POPULATIONS.
SO WE SEE ABOUT 30% OF THE KNOWN
RISK VARIANTS ARE DIFFERENT WHEN
YOU GO TO VARIED ANCESTRAL
GROUPS.
THEY'RE EITHER IN A DIFFERENT
DIRECTION OR THERE'S A DIFFERENT
UNDERLYING VARIANT.
AGAIN POINTING THIS NOTION THAT
WE REALLY NEED TO UNDERSTAND
GENETIC ARCHITECTURE IN
DIFFERENT ANCESTRAL GROUPS.
THE OTHER STORY I WANTED TO TELL
BUT IS AGAIN A VERY PRELIMINARY
STORY OR ACTUALLY IT'S A MATURE
STORY BUT IT'S EARLY ON IN THE
STUDY.
SO I TALKED A LITTLE BIT ABOUT
THE FACT THAT WE WANT TO TRAIN
INVESTIGATORS ON HOWL TO ANALYZE
THEIR DATA.
ONE OF THE WAYS WE DO THIS IS WE
HAVE TRAINING GROUPS WITH
REPRESENTATIVES FROM VARIOUS
COUNTRIES THAT COME TOGETHER AND
ANALYZE PRELIMINARY DATA.
SO ONE OF THESE WAS A GROUP THAT
WAS CENTERED AT NIH HERE AT
UNIVERSITY COLLEGE LONDON, AND
AT UNIVERSITY OF LEGOUS IN
NIGERIA, ANALYZING DATA FROM
AFRICAN ANCESTRY INDIVIDUALS
WITH PARKINSON'S DISEASE.
SO WORKING ON THIS SHARED DATA
ANALYSIS USING THE TERRA
PLATFORM REALLY IS A TRAINING
EXERCISE, DOING A GWAS IN JUST A
THOUSAND, 1500 OR SO CASES,
SOMETHING LIKE THAT, EXPECTING
TO SEE NOTHING.
WHAT HE WITH SAW WAS AN
INCREDIBLE PEAK, GENOME-WIDE
SIGNIFICANT, 10 TO THE MINUS 14,
A P VALUE OF 10 TO THE MINUS 14
ON CHROMOSOME 1.
RIGHT OVER THE TOP OF ELLEN'S
FAVORITE GENE, GBA1.
THIS WAS INCREDIBLY SURPRISING.
WE NEVER WOULD HAVE EXPECTED TO
SEE SOMETHING LIKE THIS.
AFTER A LARGE AMOUNT OF WORK,
WHAT WAS CLEARLY SHOWN IS THAT
THE SENTINAL VARIANT, THE THING
THAT'S TAGGING THIS ASSOCIATION,
IS A NON-CODING VARIANT IN THE
INTRON OF GBA1, SO NOT IN THE
PROTEIN CODING PORTION BUT IN
BETWEEN TWO AXONS.
CARRYING A SINGLE ONE OF THESE
VARIANTS INCREASES RISK ABOUT
1.3 FOLD, CARRYING TWO INCREASES
RISK ABOUT 4 FOLD.
3 1/2 TO 4 FOLD.
BUT THIS IS REMARKABLY COMMON.
ABOUT HALF OF ALL PARKINSON'S
DISEASE PATIENTS FROM NIGERIA
CARRY THIS VARIANT, AND ABOUT
ONE IN EIGHT PARKINSON'S DISEASE
PATIENTS ARE HOMOZYGOUS FOR THIS
VARIANT, PATIENTS OF AFRICAN
ANCESTRY.
SO THE POPULATION ATTRIBUTED TO
RISK, THE AMOUNT OF DISEASE
LIABILITY DRIVEN BY THIS VARIANT
IN WEST AFRICAN POPULATION IS
VERY, VERY HIGH.
EACH ALLELE YOU CARRY TEE DECRES
YOUR AGE OF ONSET BY ABOUT THREE
YEARS.
SO THE QUESTION THEN IS, WHEN WE
FIND A GENOME-WIDE SIGNIFICANT
HIT, WE HAVE TO GO AND TRY AND
UNDERSTAND WHAT IT DOING
FUNCTIONALLY, WHICH GENE IS IT
AFFECTING, HOW IS IT AFFECTING
THAT GENE.
AND THAT USUALLY TAKES QUITE A
LONG TIME.
THIS IS WORK THAT'S LED BY
CORNELIS, A PI HERE AT NIH, AND
REALLY WANTED TO ASK THESE TWO
QUESTIONS, WHAT'S THE KAU SHALL
VARIANT AND WHAT'S THE
BIOLOGICAL MECHANISM.
THIS WORK IS IN PRE-PRINT.
IT'S UNDER REVIEW AT THE MOMENT.
BUT YOU CAN GO SEE THIS WORK IN
MORE DETAIL IF YOU'RE
INTERESTED, IT'S ON MED ARCHIVE.
SO CLEARLY SOMETHING THAT THIS
VARIANT WAS ASSOCIATED WITH VERY
QUICKLY IS A CHANGE IN
EXPRESSION.
SO THE VARIANT THAT'S TAGGING AN
ASSOCIATION, THE ONE THAT'S
ASSOCIATED WITH RISK FOR
DISEASE, AND IT COULD JUST BE A
SENTINEL OR IT COULD BE "THE"
VARIANT, IS ASSOCIATED WITH
INCREASED EXPRESSION.
SO THE RISK ALLELE IS ASSOCIATED
WITH INCREASED EXPRESSION.
THAT'S KIND OF COUNTERINTUITIVE
TO WHAT WE KNOW ABOUT GBA1.
WE ASSUME NOT EVERYONE ASSUMES
BUT MANY OF US ASSUME THAT
GBA1 VARIANTS LEAD TO A LOSS OF
FUNCTION IN SOME WAY.
SO YOU WOULD HAVE EXPECTED THIS
TO BE THE OTHER WAY AROUND.
YOU WOULD HAVE EXPECTED OUR RISK
VARIANT TO LEAD TO DECREASED
GBA1 EXPRESSION.
THIS IS A COMPLICATED STORY
BECAUSE AS ELLEN HAS SAID,
GBA1 IS A COMPLICATED GENE.
THERE'S LOTS OF SPLICING GOING
ON, THERE'S A PSEUDOGENE RIGHT
NEXT TO IT, SO YOU CAN'T ALWAYS
RELY ON MEASURES OF EXPRESSION.
SO ONE OF THE NEXT THINGS THAT
WAS DONE WAS TO TAKE LONG READ
RNA SEQUENCING AND SEQUENCE
SAMPLES THAT CARRIED THIS
VARIANT.
AND WHAT YOU SHOULD SEE WHEN YOU
DO LONG READ RNA SEQUENCING IS
SEQUENCE OVER THE AXONS, RIGHT?
SO YOU'D SEE YOUR LONG STRAND OF
RNA AND IT WOULD ALIGN WITH AN
EXON, THERE WOULD BE A GAP WHERE
THERE'S AN INTRON, IT WOULD
ALIGN WITH THE NEXT AXON.
BUT WHAT WE SAW HERE IS ACTUALLY
SOME SEQUENCE IN THE INTRON.
SO THIS IS THE EXON HERE AND
THIS IS THE INTRON HERE.
SO SOMETHING IS BEING
TRANSCRIBED FROM TH THE INTRON,
TURNING INTO A PIECE OF RNA THAT
WOULD THEN EITHER BE TRANSLATED
OR DECAYED.
AND WE ONLY SAW THESE READS IN
PEOPLE WHO CARRIED THE RISK
VARIANT.
SO YOU NEVER SEE THESE REIN
ANYBODY ELSE.
READS IN
ANYBODY ELSE.
CORNELIS THEN WENT TO ASK THE
QUESTION, THE VARIANT THAT WE'RE
SEEING, IS THAT THE FUNCTIONAL
VARIANT SO THE CRISPRED THIS,
EDITED IN IN PEOPLE WHO DON'T
CARRY IT AND EDITED IT OUT IN
PEOPLE THAT DO CARRY IT.
IT COMPLETELY REVERSED -- SO THE
VARIANT WE SEE IS OUR LEAD
VARIANT FOR GWAS IS HAVING THIS
FUNCTIONAL EFFECT.
IT LEADING TO TRANSCRIPTION OF
THIS INTRONIC REGION.
SO WHEN YOU THINK ABOUT PROTEINS
BEING PRODUCED, AND THE SPLICING
OF EXONS, THERE ARE SEVERAL KEY
THINGS IN AN INTRON OR RIGHT
NEXT TO THE AXON THAT LEAD TO
SPLICING OUT OF THE INTRON AND
JOINING OF THE EXONS.
THOSE ARE THE SPLICED DONORS AND
THE SPLICED ACCEPTORS, WHICH
WE'RE ALWAYS REALLY FAMILIAR
WITH BUT THERE'S ALSO THIS
BRANCH POINT SITE WHICH OCCURS
IN MANY INTRONS.
IT'S AN A, ABOUT 40 BASE PAIRS,
BEFORE THE EXON, AND INDEED OUR
VARIANTS, THE ONE THAT IS THE
LEAD VARIANT FOR GENOME WIDE
ASSOCIATION HERE, IS THE BRANCH
POINT SITE.
SO OUR VARIANT CHANGES THIS A TO
A C.
SO WHAT THIS DOES IS DESTROY
THIS BRANCH POINT SITE AND MESS
UP SPLICING.
SO AN ALTERNATIVE BRANCH POINT
SITE SEEMS TO BEING USED,
ALTERNATIVE SPLIET SITE POINT
SEEMS TO BE USED, SO WHAT WE
ACTUALLY SEE IS PRODUCTION OF A
TRAB SCRIPT THAT WE DON'T THINK
IS BEING TRANSLATED AND THAT
LEADS US TO HAVE SOMETHING THAT
WE THINK LOOKS LIKE INCREASED
EXPRESSION.
SO YOU'VE GOT THE RISK VARIANT
THAT LEADS TO MISSPLICING.
THE MISS SPLICING LEADS TO
APPARENT INCREASE IN GB RNA BUT
WE THINK MUCH OF THAT INCREASE
IS IN TRANSCRIPTS WHICH ARE NOT
FUNCTIONAL.
WE DON'T KNOW THAT FOR SURE BUT
THAT'S WHAT WE THINK.
AND THE NET RESULT IS THEN
DECREASED GBA PROTEIN.
SO WHEN WE LOOK AT PROTEIN
QUANTITATIVE TRAIT LOCUS PLOT,
WHICH IS WHAT WE HAVE HERE ON
THE RIGHT-HAND SIDE, WE CAN SEE
THAT INDEED THAT IS THE CASE.
CARRIERS OF THE RISK GENOTYPE,
GG OR GT, HAVE LOWER PROTEIN
GBA1 LEVELS THAN THOSE WHO CARRY
THE PROTECTIVE GENOTYPE.
SO APPARENT INCREASE IN RNA BUT
NOT USEFUL RNA LEADS TO AN
APPARENT DECREASE IN PROTEIN
LEVELS.
AND THIS ALSO LEADS TO A
DECREASE IN GLUCOCEREBROSIDASE
ACTIVITY.
SO THIS WORK WAS DONE IN
COLLABORATION WITH A COMPANY
CALLED CENTEGENE, AND YOU CAN
SEE THE AFRICAN CARRIERS ON THE
RIGHT-HAND SIDE HAVE DECREASED
LEVELS OF GCASE ACTIVITY
ALTHOUGH NOT AS DECREASED AS
THOSE SEEN IN GBA CARRIERS.
AND I SHOULD NOTE THAT THIS
VARIANT NEVER CAUSES GAUCHER
DISEASE.
ELLEN MENTIONED THAT THERE ARE
SEVERAL GCASE VARIANTS THAT ARE
RISK FACTORS FOR PD OR LBD THAT
DON'T CAUSE GAUCHER'S DISEASE
AND INDEED THIS IS ONE OF THEM.
SO I THINK IDENTIFYING THE
GENETIC BASIS OF DECEMBER IS
ABSOLUTELY CRITICAL TO
UNDERSTAND BIOLOGY, AND IN SO
SUPPORTING THERAPEUTIC TARGETS.
IF WE BELIEVE THIS NOTION OF
PRECISION MEDICINE, OF TREATING
THE PATIENT AT THE RIGHT TIME
WITH THE RIGHT THERAPEUTIC, WE
NEED TO UNDERSTAND THE
MECHANISTIC BASIS OF DISEASE IN
PATIENTS ALL AROUND THE WORLD.
THIS IS WHY I THINK GP2 IS
REALLY KEY.
EVEN AT THIS PRELIMINARY STAGE,
WE'RE ONLY THREE OR FOUR YEARS
INTO THIS 10-YEAR STUDY, AND
REALLY NOW STARTING TO GET UP
AND RUNNING IN ANALYZING GENETIC
DATA.
EVEN THIS PRELIMINARY WORK SHOWS
COMBINING KAY F DATA ACROSS
POPULATIONS IS INCREDIBLY
POWERFUL, AND THAT WE CAN FIND
GENETIC ASSOCIATIONS THAT WE
WOULDN'T EXPECT IN UNDERSTUDIED
POPULATIONS.
THIS IS REALLY SUGGESTING THAT
THE WEST AFRICAN POPULATION IS
AN EXCELLENT POPULATION IN WHICH
TO CONSIDER RUNNING CLINICAL
TRIALS AGAINST GBA, THOSE
FOCUSED ON GBA ACTIVITY.
REALLY THIS IS A POPULATION THAT
WOULD NOT HAVE BEEN CONSIDERED
FOR THESE CLINICAL TRIALS UP
UNTIL THIS STUDY.
SO HOPEFULLY I'VE GIVEN YOU A
SENSE OF WHERE WE'RE HEADED.
I'M JUST GOING TO FLASH THIS UP
HERE, AND START TO TRANSFER
ELLEN OVER, BUT THIS WORK
INVOLVES AS I MENTIONED REALLY
THOUSANDS OF PEOPLE, BOTH THOSE
WITHIN THE LABORATORY OF
NEUROGENETICS, WHERE I'VE WORKED
FOR 22 YEARS WITHIN THE CENTER
FOR ALZHEIMER'S, WHERE I'VE BEEN
FOR A COUPLE YEARS, AND MORE
BROADLY, WITHIN THE GLOBAL
PARKINSON'S GENETICS PROGRAM,
WHICH AGAIN INVOLVES VERY LARGE
NUMBERS OF INDIVIDUALS AROUND
THE WORLD, AND HUNDREDS OF
THOUSANDS OF PATIENTS.
SO WE'VE GIVEN YOU A SENSE OF
WHERE WE ARE IN GENETIC
DISCOVERY, THE KIND OF INSIGHTS
THAT CAN BE MADE BY LOOKING AT
INDIVIDUAL PATIENTS, WHERE WE'RE
HEADED IN GENETIC DISCOVERY, AND
I THINK NOW WE'RE GOING TO END
WITH A DISCUSSION OF WHAT THIS
ALL MEANS FROM A THERAPEUTIC
PERSPECTIVE AND A KIND OF
EXAMPLE OF HOW THIS CAN BE
TRANSLATED.
>> GREAT.
SO THERE ARE LOTS OF DIFFERENT
APPROACHES TO THERAPEUTICS FOR
PARKINSON DISEASE, BUT WHAT I'M
GOING TO TRY TO FOCUS ON RIGHT
NOW IS WHAT WE'VE BEEN LEARNING
ABOUT GBA ASSOCIATED PARKINSON
DISEASE AND HOW WE MAY BE ABLE
TO UTILIZE THAT TOWARDS
THERAPEUTIC DEVELOPMENT.
SO THERE ARE AS I MENTIONED GOOD
GAUCHER DRUGS.
THERE'S ENZYME REPLACEMENT THAT
REVERSES THESE LARGE SPLEENS AND
MAKES OUR PATIENTS WITH TYPE
1 GAUCHER DISEASE MUCH BETTER.
THERE'S ALSO SOMETHING CALLED
SUBSTRATE REDUCTION THERAPY,
WHICH WORKS TO REDUCE PRODUCTION
OF THE SUBSTRATE AND MANY OF OUR
PATIENTS ARE DOING VERY WELL ON
THAT.
BOTH DRUGS ARE VERY EXPENSIVE,
OVER $300,000 PER PATIENT PER
YEAR.
THEY'RE INCONVENIENT, ESPECIALLY
THE ENZYME BECAUSE IT MEANS YOU
NEED AN I.V. INFUSION EVERY TWO
WEEKS, AND MOST IMPORTANTLY, FOR
PARKINSON DISEASE, IT DOESN'T
CROSS THE BLOOD-BRAIN BARRIER,
AND WE'VE HAD PATIENTS WHO HAVE
BEEN TREATED WITH ENZYME
REPLACEMENT WHO STILL DEVELOP
PARKINSONISM.
SO IT DOESN'T SEEM TO HAVE ANY
AFFECT FOR THAT.
SO THERE'S OTHER APPROACHES THAT
WE CAN THINK ABOUT, ABOUT
GETTING ENZYME TO THE BRAIN.
SOME OF THEM ARE ON THIS
DIAGRAM, A LITTLE HARD TO SEE.
ONE IS STILL ENZYME REPLACEMENT
BUT NOT JUST PERIPHERAL ENZYME
REPLACEMENT.
THERE MAY BE WAYS TO GET THE
ENZYME INTO THE BRAIN BY USING
THINGS LIKE THE TRANSFERRIN
RECEPTOR OR WHAT THEY CALL
TROJAN HORSE TYPE OF WAYS OF
GETTING PROTEINS INTO THE BRAIN.
SO THAT WOULD BE ONE WAY.
SUBSTRATE REDUCTION WAS ANOTHER
ONE THAT WAS CONSIDERED, AND IN
FACT IT WENT ALL THE WAY TO
STAGE THREE CLINICAL TRIAL, AND
IT DIDN'T WORK.
SO IT TAUGHT US SOME THINGS, BUT
IT ALSO SORT OF TAUGHT US THAT
MAYBE WE NEEDED TO KNOW A LITTLE
BIT MORE ABOUT THE BIOLOGY
BEFORE WE JUMPED THAT FAST.
A THIRD APPROACH IS -- WELL, THE
FOURTH APPROACH IS GOAN THERAPY
AND, IN FACT, THERE IS ALREADY
ONE COMPANY THAT'S TRYING GENE
THERAPY TO -- DIRECTLY TO THE
BRAIN FOR GBA PARKINSON DISEASE.
AND THE ONE THAT IS NEAR AND
DEAR TO MY HEART IS THIS NUMBER
THREE, WHICH IS CALLED ENZYME
CHAPERONES.
SO FOR, I DON'T KNOW, ALMOST 15
YEARS NOW, WE'VE BEEN FOCUSED ON
TRYING TO DEVELOP CHAPERONE
THERAPY FOR GAUCHER DISEASE, AND
NOW FOR PARKINSON DISEASE, AND
THE IDEA IS THAT OFTEN PROTEINS
ARE PL MISFOLDED, ESPECIALLY IF
THERE'S A MUTATION, BUT IF THERE
WAS A WAY WE COULD PROMOTE
FOLDING TO GET THE RESIDUAL
ENZYME INTO THE LYSOSOME, IT
MIGHT STILL BE ABLE TO FUNCTION
ADEQUATELY.
AND I THINK THAT NOW SINCE
PATIENTS WITH IDIOPATHIC
PARKINSON DISEASE ALSO MAY HAVE
LOW GLUCOCEREBROSIDASE AND THOSE
WITHOUT REALLY MUTATIONS BUT
VARIANT MAY HAVE LOWER
GLUCOCEREBROSIDASE AND EVEN WILD
TYPE PROTEINS CAN BE MISFOLDED,
IT MAY PROVIDE A THERAPEUTIC
APPROACH FOR PARKINSON DISEASE
IN GENERAL.
SO I BEGAN THIS PROJECT WHEN
NCATS WAS FIRST FOUNDED ABOUT 15
YEARS AGO.
IT'S BEEN A LONG AND FRUITFUL
COLLABORATION WITH PEOPLE THERE.
THE FIRST SCREEN WE DID WAS ONE
OF THE FIRST THAT NCATS DID.
AT THE TIME WE USED THE
RECOMBINANT ENZYME THAT'S USED
FOR THERAPY AND WE DID A SCREEN
OF A COUPLE HUNDRED THOUSAND
SMALL MOLECULES, AND WE
IDENTIFIED HITS BUT THEY WERE
MOSTLY INHIBITORY CHAPERONES
BECAUSE THAT'S WHAT YOU WOULD
PROBABLY FIND FROM A WILD TYPE
PROTEIN.
WE THEN DECIDED WE SHOULD DO A
SCREEN WITH MUTANT PROTEIN, BUT
WE DIDN'T HAVE PURIFIED MUTANT
PROTEIN, BUT WE DID HAVE THESE
ENORMOUS SPLEENS IN MY FREEZER,
SO WE TOOK A CHUNK OF THIS
MUTANT SPLEEN AND ACTUALLY USED
THAT AS THE SOURCE OF THE ENZYME
FOR A SCREEN OF ABOUT A QUARTER
OF A MILLION COMPOUNDS.
AND NOW FOR THE FIRST TIME, WE
DID IDENTIFY NON-INHIBITORY
CHAPERONES THAT WE WERE QUITE
EXCITED ABOUT.
WE HAD TWO LEAD COMPOUNDS, CALL
IT NCTC758 AND 607.
758 WAS OUT LICENSES AND
ACTUALLY IS NOW IN SOME CLINICAL
TRIALS THAT WE'RE NOT
PARTICULARLY CONNECTED TO, BUT
WE TESTED THEM IN VARIOUS
SYSTEMS AND THESE WERE SOME OF
OUR EARLY IPS -- WELL, EARLY
STUDIES WITH GAUCHER
MACROPHAGES.
WE HAD PATIENT MACROPHAGES AND
THEN IP SC MACROPHAGES, AND WE
FOUND THESE LEAD COMPOUNDS COULD
INCREASE THE ENZYME ACTIVITY,
REVERSE LIP YOU LIPID STORAGE,N
SEE BY THE FLUORESCENCE GOING
AWAY, AND RESTORE PROBLEMS OF
MACROPHAGE FUNCTION.
BUT THIS KIND OF ASSAY WAS NOT
OPTIMAL FOR DRUG DEVELOPMENT.
AND WE NEEDED TO DO LARGE SCALE
SAR AND TRYING TO GET
MACROPHAGES JUST WASN'T
FEASIBLE.
WE ALSO WANTED TO HAVE SOME KIND
OF CELL-BASED SCREEN AND SOME
KIND OF PROBE THAT LET US KNOW
WHAT WAS HAPPENING TO THE ENZYME
WHEN IT GOT TO THE LYSOSOME.
IT WASN'T ENOUGH TO SEE WHAT WAS
HAPPENING WHEN YOU HAD A CELL
EXTRACT.
SO FOR THE CELL-BASED ASSAY, WE
DID TURN TO IPFCs, PROBABLY
MOST OF YOU KNOW THE EXERCISE
WHERE YOU TAKE SKIN SAMPLE FROM
PATIENTS, MAKE A FIBROBLAST
CULTURE AND THEN REPROGRAM THE
CELLS WITH A BUNCH OF DIFFERENT
COCKTAIL OF GROWTH FACTORS AND
THEY BECOME -- INDUCE
PLURIPOTENT CELLS THAT YOU CAN
THEN DIFFERENTIATE INTO
DIFFERENT LINEAGES, AND THE
PATHOLOGICALLY RELEVANT LINAGES
FOR US HAVE BEEN CORTICAL AND
MAINLY DOPAMINERGIC NEURONS, AND
WE'VE FOCUSED ON MACROPHAGES AND
WE'RE BEGINNING TO MOVE TOWARDS
MICROGLIA ALSO.
SO FROM OUR EARLIEST STUDIES, WE
MADE NEURONAL MODELS FROM THE
FIBROBLASTS FROM PATIENTS WITH
GAUCHER DISEASE, WITH GAUCHER
AND PARKINSON TYPE 2 GOA SLAY
DISEASE, AND APPROPRIATELY WE
FOUND THAT THE DOPAMINERGIC
NEURONS WE MADE HAD DECREASED
GLUCOCEREBROSIDASE.
THEY STORED LIPID, AND WHEN YOU
TREATED THEM, THIS IS A
COLOCALIZATION WHERE GREEN IS
GLUCOCEREBROSIDASE AND RED IS
THE LYSOSOMAL MARKER.
YOU COULD SEE MUCH MORE DELIVERY
OF THE ENZYME TO THE LYSOSOME.
SO THE NEURONS RECAPITULATED
ASPECTS OF THE GAUCHER
PHENOTYPE, AND THIS PHENOTYPE
LOOKED LIKE IT COULD BE REVERSED
WITH OUR LEAD CHAPERONES, BUT
BOTH THE PURITY AND THE YIELD
WERE INADEQUATE FOR US TO
PERFORM BIG SCREENS.
SO A FEW YEARS AGO, ROBYN CHEN
JOINED MY LAB AND SORT OF
CHANGED OUR PROTOCOL.
WE NOW ARE USING SENDI VIRUS TO
MAKE THESE IPSCs.
HE'S BEEN FOCUSING ON PATIENTS
WITH GAUCHER DISEASE WITH AND
WITHOUT PARKINSON DISEASE.
AND HE'S INTRODUCED THIS
SELECTION TAG THAT ENABLES US TO
PURIFY DOPAMINERGIC CULTURES
WHERE WE CAN USE FLOW CYTOMETRY
TO GENERATE REALLY QUITE PURE
DOPAMINERGIC NEURONS FOR FURTHER
STUDY.
THE OTHER THING HE'S BEEN DOING
IS WHAT'S CALLED ISOGENIC GBA
LINES.
ONE OF THE PROBLEMS FROM OUR
FIRST STUDY IS THERE'S A LOT OF
DIFFERENCES AND GENETIC
BACKGROUND FROM PATIENT TO
PATIENT, SO IT'S KIND OF HARD TO
MAKE COMPARISONS.
SO WHAT HE DID IS HE STARTED
FROM ONE PATIENT THAT HAD
GAUCHER DISEASE AND PARKINSON
DISEASE, HE WAS MALE, COMMON IN
370 -- SN370-S GENOTYPE.
HE THEN ENGINEERED IT SO THAT
THE LINE HAD A TOTAL KNOCKOUT,
AND THEN, AND THIS WAS TRICKY
BECAUSE OF THE PSEUDOGENE, HE
MANAGED TO EDIT IT PACK SO IT
WAS WILD TYPE.
BACK SO IT
WAS WILD TYPE.
SOME STUDENTS IN THE LAB, ONE OF
WHOM IS IN THE AUDIENCE TODAY,
WORKED ON ENGINEERING IN OTHER
MUTATIONS INTO THE WILD TYPE.
SO WE HAVE THIS NOW SUITE OF
FIVE ICEGENIC LINES T ISOGENIC Y
WITH, WHICH IS USEFUL FOR
ESTABLISHING MECHANISM BUT IT'S
ALSO USEFUL FOR THERAPEUTIC
ASSAYS.
THE OTHER THING HE DID IS HE
EDITED IN A LYSOIP TAG, SO THIS
IS A TRICK WHERE YOU'RE PUTTING
IN A TAG AND THEN YOU CAN
ISOLATE LYSOSOMES VERY LIGHTLY
FROM THE CULTURES EVEN AFTER
THEY DID -- THEY'RE DECH REN
SHAITED AND SEE WHAT'S GOING ON
IN THE LYSOSOME.
WE ALSO FOCUSED SOME YEARS NOW
ON IMPROVING TOOLS WE COULD USE
FOR SCREENING.
SO I MENTIONED THAT WE NEEDED TO
HAVE A PROBE THAT TOLD US WHAT
WAS GOING ON IN THE LYSOSOME,
AND EVENTUALLY TOGETHER WITH
DAVID IN CANADA, WE HAVE BEEN
WORKING ON THIS LYSOFIX GBA
ACTIVITY PROBE, WHICH WE CAN
NICELY SEE -- IT'S QUENCHED, AND
THEN WE CAN SEE EXACTLY WHERE
THE ACTIVITY IS IN THE CELLS.
WE'VE ALSO PUT A SMALL HIBIT TAG
SO WE CAN FOLLOW WHAT'S GOING ON
WITH IT USING A LUMINESCENCE
ASSAY.
AND THIRDLY, WE DEVELOPED A NEW
ANTIBODY IN COLLABORATION WITH
ROCHE THAT'S REALLY GOOD FOR
COLOCALIZATION ASSAYS.
SO THIS IS WILD TYPE AND YOU SEE
GLUCOCEREBROSIDASE AND LYSOSOMAL
MARKER MERGING NICELY.
WHEN YOU TAKE L44P LINES, THEY
HAVE VERY LITTLE
GLUCOCEREBROSIDASE IN THE
LYSOSOME.
AND IN FACT, THIS ANTIBODY
DOESN'T RECOGNIZE ANY OF IT, BUT
WHEN IT DOES GET FOLDED
CORRECTLY, YOU ARE ABLE TO PICK
IT UP IN THE LYSOSOME, SO IT'S A
NICE VALIDATION ASSAY.
SO WE NOW THINK FINALLY AFTER
ALL THESE YEARS THAT WE HAVE THE
PIPELINE READY.
WE STARTED OFF WITH A LINE THAT
HAS L44P AND WE PARTIALLY
EDUCATED OURSELVES USING VER USL
SCREENS.
WE USED LIBRARIES NCATS HAPPENED
TO HAVE ON HAND FOR OUR FIRST
SCREENS.
WE GROW THE CELLS, WE DISPENSE
THEM, TRANSFER THE COMPOUNDS AND
THEN LOOK AT OUR READOUT WITH
THE -- FIRST WITH THE HIBIT
ASSAY AND THEN WE CAN VALIDATE
IT USING THE COLOCALIZATION WITH
THE ANTIBODY AND THE LYSOSOMAL
ACTIVITY PROBE.
IN OUR FIRST SCREENS, THIS IS
ALL DONE BY NCATS ROBOTS, WE
IDENTIFIED BOTH PHARMACOLOGIC
CHAPERONES AND PROTEOSTASIS
REGULATORS.
WE HAD HITS OF ABOUT 140 AND
THEN HAVE DONE ALL KINDS OF
SECONDARY ASSAYS ON THESE.
WE ALSO DISCOVERED THAT MAYBE
TWO DRUGS MIGHT WORK BETTER THAN
ONE.
OUR BEST CHAPERONE IS THIS
CHAPERONE WHICH MADE US HAPPY
BECAUSE IT IS VERY SIMILAR TO
ONE OF OUR OTHER CHAPERONES FROM
THE EARLIER TRIALS, AND ALL OF
THOSE WERE PICKED UP BY THIS NEW
ASSAY SYSTEM.
BUT THE OTHER THING THAT WE
WEREN'T EXPECTING IS WE PULLED
OUT A BUNCH OF PROTEOSTASIS
REGULATORS, AND IN FACT, WE'VE
DONE THESE MATRIX COMBINATION
SCREENS THAT INDICATE THAT
TOGETHER, THEY MAY FUNCTION
BETTER THAN ALONE, SO HERE YOU
CAN SEE, THIS IS ACTUALLY
LOOKING AT THE LIPIDS THAT THE
CHAPERONE 326 DECREASES LIPID
LEVELS BUT THE COMBINATION
DECREASES IT EVEN FURTHER.
SO THIS WORK IS NOW BEING
SUBMITTED TODAY, I HOPE, AND
WE'LL CONTINUE TO USE THE PIPE
LINE FOR BIGGER LIBRARIES LATER
ON AND I THINK IT'S GOING TO BE
REALLY USEFUL.
SO I THINK THAT THESE NEW TOOLS
ARE GIVING US SOME NEW
OPPORTUNITIES.
WE CAN NOW LOOK AT LYSOSOMES AT
SUBCELLULAR RESOLUTION WITH
LYSO-IP.
IT MIGHT HELP US IDENTIFY
GENETIC MODIFIERS USING THESE
ISOGENIC LINES.
WE CAN LOOK ACTUALLY AT
LYSOSOMES IN NEURONS AND IT CAN
HELP US MOVE TOWARDS NEXT
GENERATIONAL RESEARCH.
I FORGOT TO PUSH, BUT ANYWAY,
LEADING TO IDENTIFICATION OF
DISEASE-RELEVANT MECHANISMS, WE
CAN VALIDATE THEN IN ANIMAL AND
HUMAN MODELS AND CAN COME UP
WITH NOVEL TARGETS AND
THERAPIES.
SO I'D LIKE TO TELL PEOPLE, KEEP
LOOKING OUT THE WINDOWS, YOU
NEVER KNOW WHAT THE NEXT PATIENT
THAT WALKS INTO YOUR CLINIC MAY
TEACH YOU.
AND THIS CASE, STUDYING THIS
RARE DISORDER HAS PROVIDED US
INTO A REALLY NICE WINDOW INTO
SEEMINGLY UNRELATED COMPLEX
DISORDER, WHICH ULTIMATELY MAY
LEAD TO NEW THERAPIES BOTH FOR
THE RARE AND COMMON DISEASE.
AND OF COURSE THIS WORK ISN'T
DONE IN A VACUUM.
I WANT TO REALLY ACKNOWLEDGE THE
PEOPLE IN MY LAB THAT HAVE DONE
ALL THE EXPERIMENTS AND ALL THE
HARD WORK, AND MY LONG TERM
COLLABORATORS AT NCATS,
DIFFERENT NHGRI COURSE AND
TECHNOLOGY TRANSFER
COLLABORATORS AROUND THE WORLD.
AND AT NIH.
THIS TEAM THAT I HAVE WITH ASAP,
IT AN INTERNATIONAL GROUP THAT
WORKS TOGETHER AND WE RECEIVE
FUNDING IN COMMON, AND ALWAYS
I'D LIKE TO GIVE SPECIAL THANKS
TO OUR PATIENTS, THEIR FAMILY
MEMBERS, THEIR CAREGIVERS AND
REFERRING PHYSICIANS THAT MAKE
THIS KIND OF WORK POSSIBLE.
THANK YOU.
[APPLAUSE]
>> WELL, THANK YOU SO, SO MUCH
FOR THIS REALLY FANTASTIC
PRESENTATION, DR. SINGLETON AND
DR. SIDRANSKY.
SO ANYWAY, WE HAVE A VERY
INQUISITIVE GROUP ONLINE WHO
HAVE ALREADY SUBMITTED TO US
OVER A DOZEN QUESTIONS.
ENTEINTERROGATING OUR SPEAKERS.
AND SO ELLEN, WE HAVE SOME
QUESTIONS FROM THE AUDIENCE HERE
AS WELL.
WHAT'S THAT?
>> MICS ARE THERE.
>> YES, INDEED.
YES, PLEASE GO TO THE MICROPHONE
IF YOU HAVE A QUESTION THAT
YOU'D LIKE TO POSE, BUT WHILE
OUR AUDIENCE IS GOING TO THE
MICROPHONE -- HERE'S ONE.
THIS IS JUST A SIMPLE ONE.
YOU KNOW, JUST TO GET THINGS
STARTED.
SO DR. SIDRANSKY MENTIONED
SOMETHING ABOUT CHANGES IN SME
SMELLING IN PATIENTS WITH
PARKINSON DISEASE.
IS THERE ANY EXPLANATION FOR
THAT?
WHY THE PROBLEMS WITH OLFACTORY
SENSATION?
>> WELL, IT SEEMS TO BE THAT THE
NEURONS IN THAT REGION OF THE
BRAIN ARE IMPACTED.
SOMETHING THAT WE SCREEN WITH
JUST LIKE ON ONE OF THESE
SCRATCH AND SNIFF TESTS, IT
OFTEN PRECEDES THE ONSET OF THE
MOTOR SYMPTOMS OF PARKINSON
DISEASE.
BUT RIGHT NOW, WE JUST HAD A
PANDEMIC AND EVERYBODY GOT COVID
AND LOSS OF SMELL IS ALSO A
PROBLEM WITH COVID, SO I
WOULDN'T GET REALLY WORKED UP IF
YOU'RE HAVING A PROBLEM WITH
SMELLING RIGHT NOW.
IT'S COMPLICATING THE WHOLE
PICTURE.
IT'S REALLY -- WELL, SINCE THE
TASTE -- WHAT YOU TASTE IS
IMPACTED BY YOUR SENSE OF SMELL,
BUT I DON'T THINK IT AFFECTS THE
TASTE BUDS.
>> I SEE, I SEE.
ALL RIGHT.
WELL, WE HAVE A QUESTION NOW
FROM THE AUDIENCE.
>> A QUESTION AND A COMMENT.
SO TODAY I WAS VERY LUCKY, I'VE
HAD THREE LASKER AWARDEES, AND
TWO BREAKTHROUGH PRIZE WINNERS
HERE IN THE PARKINSON DISEASE.
SO MY QUESTION IS, WE ARE ALL
AFRICANS, BUT AGAIN, WE HAVE
GENETIC VARIATIONS THAT HAPPENED
WHICH ARE DIFFERENT THAN
EUROPEANS.
SO WHAT IS IT THAT HAPPENS
STARTING FROM AFRICA, THOSE
VARIANTS TAKE OVER, AND IS THERE
SOME GENETIC CHANGES THAT HAPPEN
AS WE ARE EVOLVING FROM AFRICA?
>> THERE'S NOT A SIMPLE ANSWER
TO THAT, BUT CERTAINLY
POPULATIONS OUTSIDE OF AFRICA
HAVE GONE THROUGH BOTTLENECKS
THAT HAVE REDUCED GENETIC
DIVERSITY IN THOSE POPULATIONS.
KIND OF A DIFFERENT WAY OF
ANSWERING YOUR QUESTION.
KIND OF IGNORING YOUR QUESTION
TO SUIT MY OWN NEEDS, THERE IS
SOME CONCEPT THAT SOME OF THE
GENE VARIANTS THAT ARE RISK
FACTORS FOR PARKINSON DISEASE
ARE MORE COMMON THAN ONE WOULD
EXPECT.
SO THERE IS QUITE A LOT OF
INTEREST IN UNDERSTANDING WHERE
THE MUTATIONS IN LRRK2 AND
GBA1 MIGHT CONFER SOME KIND OF
SELECTIVE ADVANTAGE PREVIOUS TO
RISK, WHETHER THERE MIGHT BE
SOME SIGNS OF SELECTION FOR, FOR
INSTANCE, RESISTANCE TO
INFECTION OR THINGS LIKE THAT.
SO YOU CAN IMAGINE THAT THERE
KIND OF RANDOM BOTTLENECK
EFFECTS WHICH CHANGES WITH
VARIANTS ARE AVAILABLE IN
DIFFERENT POPULATIONS BUT ALSO
SOME POTENTIAL DRIVERS SUCH AS
EXPOSURE TO INFECTIOUS DISEASE,
WHICH MIGHT CHANGE VARIANT
FREQUENCIES.
>> AND ALSO IT IS AMAZING, THE
LARGE NUMBER OF THESE PATIENTS,
THE VARIANTS, THEY SURVIVED.
SO IS IT PURE LUCK?
I GUESS WE ALL NEED LUCK IN SOME
WAY.
>> WHAT DO YOU MEAN, THE VARIANT
SURVIVED OR --
>> SOME OF THE PATIENTS YOU GUYS
ARE FOLLOWING, THEY NEVER
DEVELOP PARKINSON DISEASE.
SO WHAT IS IT THAT'S SAVING
THEM?
>> YEAH, WELL, ELLEN KIND OF
HINTED AT THIS AT THE BEGINNING
IN THAT WE BELIEVE THAT THE
DISEASE IS AN INTERPLAY BETWEEN
GENETICS AND ENVIRONMENT.
IT'S KIND OF THE HAND-WAVY
ANSWER TO YOUR QUESTION, ABOUT
YOU ONE WOULD SUSPECT -- WE
ALREADY HAVE EVIDENCE THAT PART
OF THE PENETRANCE OF GBA
VARIANTS AND LRRK2 VARIANTS IS
DRIVEN BY GENETICS.
WE CAN FIND MODIFIERS, SO
GENERAL GENETIC RISK VARIANTS
ALSO SEEM TO MODIFY RISK THAT'S
IMPARTED BY GBA1 AND LRRK2, BUT
THEY CERTAINLY DON'T EXPLAIN
EVERYTHING.
I TALKED A LITTLE ABOUT THE
HERITABLE COMPONENT OF DISEASE,
REPRESENTS ABOUT 30 OR 40% OF
THE TOTAL LIABILITY, SO ONLY
LIKE 30 OR 40% OF THE REASON WHY
A TYPICAL CASE HAS DISEASES IS
DUE TO HERITABLE GENETICS.
SO ONE WOULD ASSUME THAT THERE'S
SOMETHING ELSE.
THAT COULD BE ENVIRONMENT, IT
COULD BE CHANCE STOCHASTIC
EVENTS OR KIND OF RARE VARIANTS
OR MOSAIC EVENTS, BUT THE BEST
GUESS IS WHAT'S MODERATING RISK
EVEN IN MU TAKE CARRIERS IS
OTHER GENETICS AND ENVIRONMENT.
>> SO THE LAST QUESTION IS ABOUT
THTHESE PARKINSON'S PATIENTS.
DO ALL PATIENTS WITH THE
GLUCOCEREBROSIDASE -- WITH ALPHA
SYNUCLEIN, DO THEY GET BENEFITS
FROM -- THERAPY?
>> YEAH, THEY DO.
PRETTY MUCH THE SAME AS ANY RUN
OF THE MILL PARKINSON PATIENTS
DO.
>> ALL RIGHT.
CONGRATULATIONS, MORE POWER TO
YOU.
KEEP FINDING.
>> THANK YOU.
>> SO DR. ARIAS, I THINK HAS A
QUESTION.
>> FIRST OF ALL, THANK YOU FOR
REALLY AN INCREDIBLE STORY THAT
HAS BROAD IMPLICATIONS WAY
BEYOND EVEN PARKINSON'S DISEASE
THAT WE SHOULD NARROW OUR VISION
TO WHAT WE LOOK AT AND LOOK AT
THE BIG PICTURES.
SO I HAVE A QUESTION.
IT SEEMS TO ME, I RECALL THAT
PARKINSON'S DISEASE USUALLY HAS
A LONG HISTORY OF PEOPLE
BEGINNING VERY OFTEN WITH
GASTROINTESTINAL SYMPTOMS,
CONSTIPATION.
I REMEMBER A CLINICAL STUDY
WHERE SOMEBODY CLAIMED THAT
CONSTIPATION WAS ALMOST A
CONSTANT OCCURRING ANYWHERE FROM
FIVE TO 20 YEARS PERSISTENTLY
BEFORE THERE WERE NEUROLOGIC
THINGS.
SO DOES THIS HAVE IMPLICATIONS
THAT THE DISEASE ACTUALLY MAY
BEGIN OUTSIDE OF THE BRAIN?
AND AS SORT OF THE COROLLARY TO
IT, I KNOW THIS IS A BIT OF A
WILD IDEA, BUT IN ANY OF THE
ANIMAL-TYPE MODELS, IS IT
TRANSMISSIBLE OR ARE YOU DEALING
WITH SOMETHING LIKE A PRION THAT
COULD BE ACTIVATING THIS SYSTEM
THAT YOU DESCRIBE, PARTICULARLY
IN THE PRESENCE OF RISK FACTORS?
>> YEAH, SO -- WELL, WHAT I'M
ABOUT TO SAY, I DON'T KNOW THAT
THERE'S -- THERE'S REALLY STRONG
EVIDENCE IN FAVOR OR AGAINST,
BUT THERE'S A HUGE AMOUNT OF
INTEREST IN THIS NOTION THAT
SYNUCLEIN MIGHT ACT A BIT LIKE A
PRION.
I THINK WE HAVE TO BE CAREFUL
WITH THE USE OF THE WORD
TRANSMISSIBLE.
I DON'T THINK THAT THIS IS A
TRANSMISSIBLE DISEASE IN THE
SAME WAY THAT A PRION IS, LIKE
CURO OR ANYTHING LIKE THAT.
BUT THERE IS A NOTION THAT A
COMPONENT OF THIS MIGHT BE
CELL-TO-CELL TRANSFER AND
PERMISSIVE TEMPLATING.
SO A MALFORMED STRAIN OF SIGH
KSYNUCLEIN LEADS TO THE CREATION
OF MORE MALFORMED STRAINS OF
SYNUCLEIN AND SO FORTH.
PART OF THIS IS DRIVEN BY YOUR
COMMENT EARLIER AROUND THE FACT
THAT YOU CAN SEE PROBLEMS IN THE
GUT AND THAT YOU SEPA THOLG IN Y
IN THE GUT PRETTY EARLY ON.
SO ONE OF THE QUESTIONS EARLIER
WAS ABOUT ANOSMIA AND SMELL.
ANOSMIA SEEMS TO BE AN EARLY
FEATURE, TIGHTLY ASSOCIATED WITH
A FAIRLY NEW ASSAY CALLED
SYNUCLEIN SEEDING AMPLIFICATION
ASSAY, WHICH IS LIKE A PCR FOR
MALFORMED SYNUCLEIN.
SO YOU CAN SEE THE SYNUCLEIN
AGGREGATE ASSAY POSITIVITY IN
PEOPLE WELL BEFORE THEY GET
DISEASE.
YOU ALSO SEE OTHER FEATURES LIKE
REM SLEEP BEHAVIORAL DISORDER,
THAT'S PRETTY YON.
COMMON,
CONSTIPATION, LOTS OF
DISAUTONOMIC FEATURES, LOTS
GOING ON.
>> A BIG KIND OF CONTROVERSY,
BRAIN FIRST, BODY FIRST, BUT
THERE IS A LOT OF EVIDENCE FOR
THE BODY FIRST PART.
ALSO CARDIAC INNERVATION AND
THOSE STUDIES FROM DR. GOLDSTEIN
ARE ALSO SUGGESTING THAT YOU CAN
SEE PRODROMAL PARKINSON THAT
WAY.
THE SPREAD ACTUALLY HAS BEEN
DOCUMENTED IN ANIMAL MODELS,
WHERE IF YOU DO INJECT FIBRILS
OF SYNUCLEIN, YOU CAN INDUCE A
PARKINSON TYPE OF DISEASE.
>> ONE OF THE DRIVERS -- SO THIS
IDEA HAS BEEN AROUND FOR QUITE A
WHILE.
I WOULD SAY IT WENT DORMANT FOR
A NUMBER OF YEARS, AND SOMETHING
THAT RE-ENERGIZED IT A LITTLE
BIT WAS A COUPLE OF PAPERS, ONE
FROM JEFF CORDOV AND ONE FROM
PATRICK BRUNDIN WHICH SHOWS THAT
IN PATIENTS WHO RECEIVED FETAL
TRANSPLANT, DOPAMINERGIC
NEURONS, MANY YEARS LATER, AT
AUTOPSY, YOU SEE LEWY BODIES IN
THE TRANSPLANT.
SO THIS KIND OF STARTED TO
REVITALIZE THIS IDEA OF SPREAD
THAT YOU COULD HAVE THIS
PATHOLOGIC SPECIES THAT SPREADS
FROM TISSUE TO TISSUE.
>> SO ALONG THOSE LINES THEN,
ARE THERE ANY DATA WITH REGARD
TO FAMILY MEMBERS, YOU KNOW,
SPOUSES AS OPPOSED TO
GENETICALLY RELATED FAMILY
MEMBERS WHERE THEY CATCH IT?
>> NO, NO EVIDENCE OF
TRANSMISSIBILITY IN THAT WAY
OUTSIDE OF THE GERMLINE.
>> ALL RIGHT.
WELL, HERE WE HAVE ANOTHER
QUESTION FROM THE AUDIENCE.
SO WHAT IS THE ROLE OF
INFLAMMATION IN PARKINSON
DISEASE, AND HAVE ANY SPECIFIC
CYTOKINE INHIBITORS EVER BEEN
TESTED IN PATIENT WITH
PARKINSON'S?
EXPWR THE
>> THERE'S NO QUESTION THAT IB T
INFLAMMATION, MICROGLIA,
ASTROCYTOSIS IS SEEN IN THE
BRAIN IN ANIMALS WITH
PARKINSON'S DISEASE, BUT WE
DON'T KNOW ABOUT THE THERAPY
QUESTION.
SORRY.
>> FROM A GENETIC PERSPECTIVE,
SO ONE OF THE THINGS THAT WE'VE
BEEN DOING IS TO COMBINE GENETIC
DATA AND SINGLE CELL EXPRESSION
DATA TO TRY AND UNDERSTAND WHAT
THE CELLULAR CONTEXT OF GENETIC
RISK LO LOOKS LIKE.
WHEN YOU LOOK AT A DISEASE, IT
VERY CLEAR THERE'S A MONOCYTE --
NOT COMPLETELY BUT MAINLY
DOPAMINERGIC -- MAYBE ASTROCYTE
COMPONENT TOO.
SO I THINK IT'S A MIX OF THINGS
TO BE HOB EL HONEST.
>> HERE'S ANOTHER QUESTION FROM
THE AUDIENCE.
SO YOU HAVE HIGHLIGHTED THE
POSSIBLE GENETIC OVERLAP BETWEEN
PARKINSON DISEASE AND LEWY BODY
DEMENTIA.
SO IS THERE ANY GENETIC OVERLAP
WITH THINGS LIKE BIPOLAR
DISORDER OR SCHIZOPHRENIA?
>> WE DON'T REALLY SEE MUCH, SO
WE'VE LOOKED AT -- IN TERMS OF
COMPLEX GENETICS.
SO IN TERMS OF LOOKING AT THE
CUMULATIVE RISK FACTORS
IDENTIFIED IN DISEASES LIKE
SCHIZOPHRENIA, BIPOLAR,
PARKINSON'S, ALZHEIMER'S, WE
DON'T SEE A LOT OF OVERLAP.
THERE'S THERE ARE SOME THINGS
LIKE HLA IS COMMON BETWEEN PD
AND ALZHEIMER'S DISEASE, BUT
ASIDE FROM THAT, NOT A HUGE
AMOUNT OF OVERLAP, AND CERTAINLY
NOT WITH MENTAL HEALTH DISORDERS
YOU MENTIONED.
>> SO YOU MENTIONED HLA.
SO IS THIS CLASS 1, CLASS 2,
CLASS 3, OR DOES ANYONE KNOW AT
THIS POINT?
>> WE DON'T KNOW.
AS YOU KNOW, IT'S KIND OF A
COMPLEX REGION TO DISSECT
GENETICALLY.
AND I WOULD SAY THE FIELD IS HAS
KIND OF STAYED AWAY FROM IT A
LITTLE BIT.
IT'S A FAIRLY MILD RISK FACTOR
SO WE DON'T REALLY KNOW A HUGE
AMOUNT.
>> SO IT'S NOT THE SAME SKY
SKYSCRAPER OF THE MANHATTAN PLOT
THAT ONE SEES WITH SOME OF THE
MOTHER CLASSIC AUTOIMMUNE
DISEASES.
>> NO, NO, NO, IT IS -- IF YOU
DO ANY KIND OF GENETIC
ASSOCIATION IN PARKINSON'S
DISEASE, THE FIRST THING YOU SEE
IS SYNUCLEIN ALWAYS.
THAT'S THE NUMBER ONE HIT ON
A -- THAT'S THE SKYSCRAPER, TAW
IS USUALLY THE SECOND ONE, BUT
ONLY IN NORTHERN EUROPEAN
POPULATIONS.
HLA DOESN'T REALLY POP UP UNTIL
YOU'RE WELL DOWN THE LIST.
>> I SEE.
I SEE.
ALL RIGHT.
SO THEN YOU'VE SORT OF TOUCHED
UPON THIS A LITTLE BIT WITH
REGARD TO SLEEP, BUT THIS
QUESTION SORT OF CAME FROM, I
THINK, THE OPPOSITE DIRECTION.
WHAT'S THE ROLE OF SLEEP IN
PARKINSON DISEASE
PREDISPOSITION?
IN OTHER WORDS, IF YOU WERE TO
SLEEP DEPRIVE SOMEONE, WOULD
THAT INCREASE THEIR RISK OF
PARKINSON DISEASE?
INTO I DON'T KNOW IF WE REALLY
HAVE DATA ON THAT.
WE DO KNOW THAT THIS ALTERED
SLEEP, REM SLEEP DISORDER IS
KIND OF WHEN YOU'RE ACTING OUT
YOUR DREAMS OR YOU MIGHT SOCK
YOUR SPOUSE OR SOMETHING.
THAT IS VERY WELL CORRELATED
WITH THE ODDS OF DEVELOPING
PARKINSON DISEASE.
DOES IT HELP -- IS IT PROTECTIVE
TO GET MORE SLEEP?
IT'S ALWAYS GOOD TO GET MORE
SLEEP.
BUT WE TELL OUR PATIENTS WHAT'S
REALLY GOOD FOR THEM IS
EXERCISE.
>> OKAY.
HERE'S -- OH, I THINK WE HAVE
ONE AT THE MICROPHONE THERE.
>> I KNOW THE TALKS HAVE BEEN
FOCUSED ON GENETIC COMPONENTS OF
PARKINSON DISEASE.
HOWEVER, WE WOULD LOVE TO HEAR
YOUR OPINION ON THE EXPOSURE TO
DTT, TO OTHER PESTICIDES, AND
HOW THAT INTERPLAYS PERHAPS IN
SOME OF THE PARKINSON DISEASE
BOTH INCIDENCE AS WELL AS
THERAPEUTIC OUTCOME.
>> DO YOU WANT TO TAKE THIS?
OKAY, THANKS.
SO THERE'S BEEN QUITE A LOT OF
EPIDEMIOLOGICAL WORK, ALTHOUGH
THE NICE THING ABOUT GENETICS IS
IT'S LARGE BUT FINITE, AND
FAIRLY EASY TO MEASURE.
THE ENVIRONMENT IS MUCH MORE
DIFFICULT TO MEASURE.
I THINK THERE'S A LOT THAT NEEDS
TO BE DONE BUT THERE'S CERTAINLY
VERY INTRIGUING ASSOCIATIONS
WITH SMOKING, CAFFEINE, DRINKING
OF WELL WATER, EXPOSURE TO
PESTICIDES, SOME OF THOSE STUDY,
I ACTUALLY KIND OF -- SIMILAR TO
ELLEN'S EXPERIENCE REALLY JUST
LOOKING AT A SMALL NUMBER OF
PATIENTS AND THEN GOING OUT FROM
THERE.
ONE OF THE EARLY STUDIES WAS
DONE BY A GUY CALLED BILL LOS
ANBILLLANGSTON WHO OBSERVED
PARKINSON'S DISORDER IN PATIENTS
WHO HAD USED SYNTHETIC HEROIN
THAT LED TO DEATH OF
DOPAMINERGIC NEURONS AND THIS
LED TO THIS WHOLE HYPOTHESIS
ABOUT TOXICITY AND EFFECT ON
COMPLEX ONE INHIBITION.
SO THIS HAS LED TO A WHOLE BUNCH
OF INVESTIGATION AROUND
POTENTIAL EXPOSURES AND THEIR
LINK TO DISEASE.
I HONESTLY THINK WE JUST DON'T
REALLY HAVE ENOUGH DATA RIGHT
NOW.
ONE OF THE THINGS WE'RE TRYING
TO TOUCH ON IN GP2 IS TO HAVE A
UNIFIED EXPOSURE QUESTIONNAIRE.
IT'S NOT MUCH BUT IT'S SOMETHING
THAT CAN BE APPLIED TO ALL OF
THE POPULATIONS THAT WE'RE
STUDYING.
MAYBE THAT WILL START TO GIVE US
SOME ANSWERS.
CERTAINLY MANY GROUPS HAVE
ROOKED AT GENE INTERACTION BY
VIERT BUT THERE'S REALLY NOTHING
COMPELLING TO BE HONEST.
>> MAYBE JUST TO FOLLOW THAT
ENVIRONMENTAL THEME A LITTLE BIT
FURTHER, ANY ROLE FOR DIET, IN
TERMS OF INCREASING RISK OR
MAYBE IN SOME WAY AVERTING
PARKINSON DISEASE?
>> NOTHING THAT'S REALLY --
NOTHING THAT'S REALLY COMPELLING
TO BE HONEST.
>> THERE ISN'T THAT I KNOW OF
EXCEPT IT'S OKAY TO DRINK A LOT
OF COFFEE.
IT'S SUPPOSED TO BE PROTECTIVE.
>> OH, DRINK A LOT OF COFFEE?
OH.
WELL.
>> I'M JUST SAYING THAT TO YOU
BECAUSE YOU KNOW THAT'S WHAT YOU
DO.
>> I'M IN GOOD SHAPE.
OKAY.
ALL RIGHT.
SO THEN ANOTHER MEMBER OF THE
AUDIENCE WOULD LIKE TO KNOW
SOMETHING ABOUT IMPLANTABLE
ELECTRICAL STIMULATION AND ITS
THERAPEUTIC ROLE IN PARKINSON'S.
>> DBS.
>> YOU'RE TALKING ABOUT DBS?
SO PEOPLE WHO -- IT IS A
REALLY -- FOR SOME PEOPLE IT
HELPS THEM A LOT.
IT'S USUALLY PEOPLE AT THE STAGE
WHERE THEY'RE STILL RESPONDING
TO DOPAMINE, FURTHER ON LATE
STAGE, IT'S LESS GOOD.
IT IS -- YO UNIVERSALLY -- IT
DOESN'T ALWAYS WORK, SO I THINK
THERE ARE CERTAIN CRITERIA THAT
NEUROSURGEONS USE IN ORDER TO
DECIDE WHO'S GOING TO BE A GOOD
CANDIDATE, BUT IN THOSE
PATIENTS, SOMETIMES IT GIVES
THEM QUITE A FEW YEARS OF
IMPROVED LIFE QUALITY.
>> OKAY.
ALL RIGHT.
LET'S SEE.
WHAT OTHER QUESTIONS?
ANOTHER MAYBE ENVIRONMENTALLY
RELATED QUESTION.
WHAT IS THE ROLE OF STRESS IN
PARKINSON DISEASE PREDISPOS
PREDISPOSITION?
>> HARD TO MEASURE.
I DON'T KNOW --
>> WE'RE ALL STRESSED.
>> I ALWAYS THINK A LITTLE
STRESS IS GOOD, A LOT OF STRESS
IS BAD.
>> ALL RIGHT.
WELL, THAT'S WORDS OF WISDOM.
[LAUGHTER]
>> I'M NOT SURE IT IS.
>> SO HERE'S ANOTHER ONE.
THAT JUST CAME IN OVER THE WIRE.
IN RECENT DECADES, NUMEROUS
STUDIES HAVE FOUND THAT SMOKING
OR THE INTAKE OF ANY FORM OF
NICOTINE, SUCH AS SMOKELESS
TOBACCO, EXPOSURE TO
ENVIRONMENTAL TOBACCO SMOKE, OR
EVEN DIETARY SOURCES SUCH AS
PEPPERS, REDUCES THE RISK OF
DEVELOPING PARKINSON'S DISEASE.
HAS THIS BEEN DISCREDITED?
>> WELL, IT'S AN EPIDEMIOLOGIC
FINDING.
IT'S CERTAINLY NOT SOMETHING
ANYBODY WOULD PRESCRIBE.
YOU CAN END UP DYING FROM CANCER
BEFORE YOUR PARKINSON WILL GET
TO YOU.
IT LIKE THE COFFEE STORY.
YOU KNOW, IF YOU LOOK AT BIG
POPULATIONS AND DO SURVEYS,
SMOARKS TEND TO HAVE A LITTLE
BIT LESS, SOME PEOPLE EVEN
SUGGESTED BACK TO YOUR PREVIOUS
QUESTION, THAT THERE'S A CERTAIN
BEHAVIORAL PHENOTYPE OF PEOPLE
WHO ARE MORE LIKELY TO BE LESS
RISK TAKERS THAT TEND TO HAVE
PARKINSON DISEASE, SO MAYBE THE
SMOKERS ARE THE MORE RISK --
IT'S REALLY GOING TO BE HARD TO
TEASE OUT.
>> YEAH, YOU CAN IMAGINE WITH A
DISEASE OF DOPAMINE AND DOPAMINE
BEING SO HEAVILY INVOLVED IN THE
REWARD SYSTEM THAT THIS COULD BE
PART OF A PREMORBID PERSONALITY
DISORDER.
SO WE KNOW THAT DISEASE IS
ONGOING FOR PROBABLY DECADES
BEFORE A PATIENT SHOWS CLINICAL
SIGNS AND SYMPTOMS, SO WHAT THEY
DO IN THOSE DECADES BEFORE COULD
CERTAINLY BE INFLUENCED BY THE
DISEASE PROCESS RATHER THAN THE
OTHER WAY AROUND.
>> YES, YES.
OKAY.
SO HERE'S ONE WHICH I THINK GOES
ALONG WITH SOME OF THE GLOBAL
STUDIES THAT YOU'VE SPOKEN
ABOUT.
THE QUESTION IS, ARE THERE ANY
PART OF THE WORLD WHERE THERE'S
AN ESPECIALLY HIGH RISK OR
FREQUENCY OF PARKINSON'S
DISEASE?
>> YEAH, SO THIS -- REALLY THE
WAY TO DO THIS IS THAT DOOR TO
DOOR EPIDEMIOLOGICAL SURVEYS OR
IF THEY'RE CENTRALIZED
HEALTHCARE SYSTEMS.
AND THERE ARE NOT MANY OF EITHER
OF THOSE THINGS TO ALLOW YOU TO
REALLY GET GREAT ESTIMATES OF
THIS.
WE CERTAINLY KNOW THAT THERE ARE
RISK VARIANTS THAT ARE MUCH MORE
COMMON IN SOME POPULATIONS THAN
OTHERS.
WE TALKED ABOUT LRRK2.
40% OF NORTH AFRICAN ARABS WITH
PARKINSON'S DISEASE CARRY THAT
MU TAKE.
WE TALKED ABOUT THE ASHKENAZI
JEWISH POPULATION, SO I WOULD
SAY THAT WE KNOW THAT THAT'S
TRUE.
WE DON'T KNOW BEYOND ANECDOTE
WHETHER THERE ARE CERTAIN
ANCESTRAL GROUPS OR AREAS OF THE
WORLD WHERE THE DISEASE IS MORE
COMMON OR LESS COMMON THAN ONE
WOULD EXPECT.
>> SO WHAT ARE THE CRITERIA FOR
A CLINICAL TRIAL IN PATIENTS
WITH PARKINSON'S DISEASE?
WHAT IS THE THINKING ABOUT AT
WHAT STAGE OF THE DISEASE WOULD
YOU WANT TO INTERVENE, AND HOW
WOULD YOU DETERMINE WHETHER
YOU'RE HAVING A BENEFICIAL
EFFECT?
>> GREAT QUESTION.
>> MILLION DOLLAR QUESTION.
THE BEST WOULD BE IF YOU COULD
IDENTIFY PATIENTS IN THE
PRODROMAL PERIOD, AND THAT'S WHY
WE'RE SO ACTIVELY LOOKING AT
BIOMARKERS OR GENES OR THINGS
THAT -- IF YOU CAN FIND THE
EARLIEST DIAGNOSIS TO PREVENT
LOSS OF DOPAMINERGIC NEURONS,
THAT WOULD PROBABLY BE THE BEST
APPROACHMENT APPROACH.
RIGHT NOW THEY USE SCALES OF
MOVEMENT PROBABLY TRIALS SHOULD
BE NOT TOO LATE IN THE DISEASE.
>> THE PROBLEM IS THE SCALES ARE
NOT -- THE SCALES ARE NOT ALWAYS
PARTICULARLY REPRODUCIBLE.
AND IT CAN BE A SLOWLY
PROGRESSING DISEASE, SO THIS
MEANS THAT TRIALS CAN TAKE A
VERY LONG TIME, MEANING THEY'RE
VERY EXPENSIVE.
I THINK THERE'S A MOVE MORE AND
MORE, AND I THINK WE SEE THIS IN
OTHER NEURODEGENERATIVE
DISEASES, TO TRY AND DEFINE THE
DISEASE BY ITS UNDERLYING
BIOLOGY RATHER THAN IT'S
CLINICAL SIGNS AND SYMPTOMS.
SO THIS IS PART OF THE RATIONALE
FOR TRYING TO FIND EARLY
PRE-CLINICAL BIOMARKERS THAT YOU
COULD USE AS A READOUT FOR SOME
KIND OF THERAPEUTIC SUCCESS.
>> IT WOULD BE GREAT IF THEY
WERE MORE PENETRANT.
>> YEAH, IT WOULD MAKE THINGS
EASIER.
>> SO ALONG THOSE LINES,
POLYGENIC RISK SCORE, ARE THERE
POLYGENIC RISK SCORES THAT NOW
ARE CALCULATED AND --
>> YEAH, THERE ARE POLYGENIC
RISK SCORES.
THEY DO OKAY.
THEY DO FAIRLY WELL WHEN
COMBINED WITH OTHER FEATURES
LIKE SEX, FAMILY HISTORY,
ANOSMIA.
ANOSMIA IS A GREAT PREDICTOR OF
DISEASE.
REM SLEEP, BEHAVIORAL DISORDER.
WHEN YOU COMBINE THOSE THINGS,
YOU GET FAIRLY HIGH PREDICTIVE
POWER.
>> SO THOSE INDIVIDUAL THEN THAT
HAVE A HIGH POLYGENIC RISK SCORE
AND HAVE ANOSMIA, THEY MIGHT BE
CANDIDATE IF ONE HAD SOME SORT
OF A PREVENTIVE --
>> BUT THEN AGAIN, THAT'S GOING
TO BE REALLY LONG TRIALS AND IT
GOING TO BE HARD TO DECIDE
WHETHER YOUR INTERVENTION MADE
THE DIFFERENCE OR WHETHER THEY
WERE -- HOW PREDICTIVE IT REALLY
IS.
>> I WOULD SAY FROM A FARMER
PERSPECTIVE, THE THING THAT WE
GET ASKED A LOT WITHIN GP2 IS
CAN YOU PROVIDE PRECISION
COHORTS FOR FUTURE TRIALS, CAN
YOU PROVIDE COHORTS WITH THIS
PARTICULAR MOLECULAR FLAVOR OF
DISEASE, CAN YOU PROVIDE COHORTS
WITH THIS PARTICULAR MUTATION.
>> OKAY, ANOTHER QUESTION.
CAN YOU SAY ANYTHING MORE ABOUT
THE ANIMAL MODELS OF PARKINSON
DISEASE, AND DO THEY PROVIDE --
YOU'VE SPOKEN A LITTLE BIT ABOUT
ANIMAL MODELS, BUT MAYBE JUST TO
AMPLIFY A BIT.
>> I THINK THEY'VE BEEN USEFUL.
I THINK THE MISTAKE THAT WE'VE
OFTEN MADE AS A FIELD IS TO TRY
AND RECAPITULATE THE CLINICAL
DISEASE RATHER THAN TO USE
MODELS TO UNDERSTAND THE
MOLECULAR -- INDIVIDUAL
MOLECULAR BASIS OF DISEASE.
I THINK IF WE THINK ABOUT THEM,
ELLEN TALKED A LITTLE ABOUT THIS
EARLIER WITH THE
TRANSMISSIBILITY EXPERIMENTS.
IF WE THINK ABOUT THEM FOR
TESTING INDIVIDUAL MECHANISTIC
IDEAS, THEY'VE BEEN GOOD.
IF YOU THINK ABOUT THEM TO
RE-CREATE THE DISEASE AS A
WHOLE, THEY'VE JUST NOT BEEN
PARTICULARLY SUCCESSFUL.
>> ALL RIGHT.
ANOTHER NEW QUESTION THAT JUST
CAME IN, THE MICROBIOME.
ANY DATA WITH REGARD TO THE
MICROBIOME AND ITS RELATIONSHIP?
>> IT'S THE HOT TOPIC.
>> YEAH, IT'S A REALLY EARLY
FIELD IN PARKINSON'S DISEASE.
IT'S A REALLY EARLY FIELD.
I WOULD SAY THAT PRELIMINARY
WORK FOR MICROBIOME HAS BEEN
SUPERFICIAL BUT OUT OF NECESSITY
BECAUSE THAT'S WHERE YOU START,
SO CHARACTERIZING GROUPS OF
MICROBIOTA RATHER THAN GOING
INTO MORE DETAIL.
THERE IS CERTAINLY A MOVE TO
CERTAINLY MORE DETAILED WORK IN
THE MICROBIOME.
ASAP IS SPOB SOARING A LARGE
MICROBIOME EFFORT.
SO A LITTLE CONFOUNDED, BECAUSE
PARKINSON'S PATIENTS ARE
CONSTIPATED.
SO HOW DO YOU CONTROL FOR THAT.
THEIR MICROBIOME IS PROBABLY
DIFFERENT BECAUSE OF THE
CONSTIPATION, AND NOT AS A
DRIVER OF DISEASE.
SO CONTROLLING FOR THAT CAN BE A
LITTLE DIFFICULT.
>> OKAY.
ANOTHER QUESTION THAT ACTUALLY
JUST CAME BY CARRIER PIGEON.
ASSOCIATION WITH COVID-19.
>> AHH, YEAH, TOUGH ONE.
WE DON'T KNOW.
SO I WOULD SAY THAT WE'VE BEEN
DOING SOME WORK BROADLY IN
NEURODEGENERATIVE DISEASE TO
LOOK AT VIRAL INFECTION AS A
RISK FACTOR FOR ALZHEIMER'S,
PARKINSON'S, FRONTOTEMPORAL
DEMENTIA, AND CERTAINLY WE SEE
AN ASSOCIATION BETWEEN VERY
SEVERE INFECTION, SO SEVERE THAT
YOU HAVE TO BE HOSPITALIZED, AND
I'M NOT TALKING ABOUT COVID
HERE, I'M TALKING ABOUT OTHER
INFECTIONS, AND SUBSEQUENT RISK
FOR NEURODEGENERATIVE DISEASE,
10, 15 YEARS DOWN THE LINE.
I THINK THAT WORK, THERE NEEDS
TO BE FURTHER ANALYSIS IN THAT
SPACE, AND AGAIN YOU CAN USE
BIOBANK DATA TO DO THIS.
COVID-19, WE DON'T SEE MUCH IN
TERMS OF GENETIC ASSOCIATION
BETWEEN THE TWO.
SO WHEN WE LOOK AT WHAT ARE
DRIVERS FOR SEVERITY ORIS BEING
OF COVID-19 AND THOSE FOR
PARKINSON'S DISEASE, WE DON'T
REALLY SEE MUCH OVERLAP THERE,
BUT WHETHER THERE'S GOING TO BE
ANY INCREASED RISK BECAUSE OF
COVID-19, I DON'T KNOW, IT'S TOO
EARLY TO SAY, BUT CERTAINLY
INTERESTING.
>> ALL RIGHT.
ANOTHER QUESTION IS SORT OF
FOLLOWING UP ON A DISCUSSION
THAT WE HAD LAST WEEK, IN THE
SESSION.
IS THERE ANY RELATIONSHIP
BETWEEN PRIOR STROKE OR OTHER
NEUROLOGIC DAMAGING DISEASES
LIKE MULTIPLE SCLEROSIS AND THE
DEVELOPMENT OF PARKINSON'S
DISEASE?
>> I THINK THERE IS SOMETHING
CALLED VASCULAR PARKINSONISM.
I'M NOT SURE THAT THE MECHANISM
IS THE SAME.
I THINK THAT'S THE ONLY THING I
COULD SAY ABOUT THAT.
>> PRETTY UNRELATED.
>> SO IT'S A RELATIVELY SMALL
PERCENTAGE OF PEOPLE THAT
PRESENT WITH CLINICAL
PARKINSONISM.
>> YEP.
>> OKAY.
SO THEN WE'RE GETTING TOWARDS
THE END OF THE LIST OF QUESTIONS
HERE FROM THE AUDIENCE.
YOU MENTIONED PROTEOSTASIS.
ARE THERE ANY DATA WITH REGARD
TO PATIENTS THAT ARE ON
PROTEOSOME INHIBITORS, FOR
EXAMPLE, AND WHETHER OR NOT THEY
DEVELOP THE CLINICAL PICTURE OF
PARKINSONISM?
>> I DON'T KNOW OF ANY DATA.
>> ALL RIGHT.
WELL, MORE QUESTIONS.
OH, BOY.
IN THE BACK.
YES, I'D NEED A MIRROR SO THAT I
CAN SEE IN THE BACK.
>> SORRY.
I HOPE IT'S OKAY THAT I JUST
GRABBED THE MIC.
>> IT GREAT.
>> OKAY.
I JUST HAD A QUESTION REGARDING
GAUCHER AND THE DIFFERENT TYPES
AND THE AMOUNT OF NEUROPATHOLOGY
THAT YOU SEE.
DO YOU BELIEVE THAT HAS TO DO
WITH SOMATIC MOSAICISM AND THE
AMOUNT OF NEURAL LYSOSOMES
AFFECTED OR NEUROINFLAMMATION?
DO YOU HAVE ANY IDEAS WITH
REGARDS TO WHAT SEPARATES --
>> I WISH I DID.
I THINK IT'S MOST LIKELY THAT --
FIRST OF ALL, THE INITIATIONS DO
HAVE SOME IMPACT.
THERE'S SOME MUTATIONS.
IF YOU HAVE TWO NULL MUTATIONS
YOU PROBABLY WILL HAVE THE ACUTE
NEURONEURONOPA THICK FORM.
IT IS DIFFICULT TO SEE, THERE IS
A LOT OF NEUROINFLAMMATION IN
THE BRAIN OF NEURONOPA THICK
GAUCHER DISEASE.
WE THINK THAT IT'S PROBABLY SOME
KIND OF GENETIC MODIFIERS THAT
WE JUST HAVEN'T YET IDENTIFIED.
THERE'S PROBABLY MANY OTHER
GENES THAT WORK IN CONCERT.
>> THANK YOU.
>> WE CERTAINLY KNOW THAT IF YOU
TAKE THE POLYGENIC RISK SCORE
FOR JUST TYPICAL PARKINSON'S
DISEASE AND YOU OVERLAY THAT ON
A GAUCHER'S MUTATION, IT
INCREASES YOUR RISK OF
PARKINSON'S DISEASE OR
PARKINSON'S PATHOLOGY IN THOSE
CARRIERS.
SO CERTAINLY MECHANISTICALLY,
THOSE ARE LINKED.
>> SO ANCIENT HISTORY, I MEAN,
FOLLOWING THE GREAT PANDEMIC OF
INFLUENZA, THERE WAS SOMETHING
KNOWN AS POST INFLUENZAL
PARKINSON'S DISEASE, WHICH
SEEMED TO ATTRACT A GOOD BIT OF
ATTENTION FOR A LARGE NUMBER OF
YEARS, AND THEN WAS SORT OF PUT
TO REST.
I THINK LARGELY BY EPIDEMIOLOGIC
STUDIES BUT I'M NOT SURE.
BUT IN VIEW OF YOUR FINDINGS OF
RISK FACTORS AND WHAT NOT, IS IT
CONCEIVABLE THAT SOME OF THAT
INFORMATION CAN BE RE-EXAMINED
TO EXAMINE THE POSSIBILITY THAT
THOSE WHO WERE AFFECTED -- I
MEAN, OBVIOUSLY YOU DON'T HAVE
THE TISSUES -- DR. TAUBENBERGER
HAS TISSUES FROM SOME OF THOSE
PATIENTS BUT NOT THE
PARKINSON'S.
>> YEAH, IT WOULD BE GREAT TO BE
ABLE TO ACCESS GENETIC MATERIAL.
SO THAT AS FAR AS I UNDERSTAND
IT WAS A TAUOPATHIES RATHER THAN
A SI SYNUCLEINOPATHY.
ONE OF THE THINGS WE DIDN'T TALK
ABOUT TODAY WAS LRRK2 PATIENTS,
SO PATIENTS WHO CARRY A
LRRK2 MUTATION, WHILE THEY MAY
LOOK CLINICALLY LIKE THEY'RE
PARKINSON'S DISEASE, ONLY ABOUT
70% OF THEM HAVE A
SYNUCLEINOPATHY.
SOME OF THEM HAVE A TAUOPATHY,
SOME HAVE SOME OTHER TYPE OF
PATHOLOGY.
SO MORE BROADLY UNDERSTANDING
WHAT TRIEFS THESE DIFFERENT DRIT
PATHOLOGIES, THE DIFFERENCE
BETWEEN SOMEONE WHO HAS A TD
TDB40OPATHY OR -- IS REALLY
FASCINATING.
THE POST ENCEPHALITIS
PARKINSONISM WOULD BE A REALLY
INTERESTING PLACE TO LOOK.
>> ALL RIGHT.
WELL, THE QUESTIONS JUST KEEP
FLOWING IN.
SO WE NOW HAVE A QUESTION WITH
REGARD TO THE ENDOCRINE SYSTEM
AND WHETHER OR NOT THERE ARE
AGE-RELATED CHANGES IN HORMONAL
FUNCTION SUCH AS HYPOTHYROIDISM
AND THE RISK FOR DEVELOPING
PARKINSON DISEASE.
>> THAT'S ALL YOU, ELLEN.
>> I DON'T KNOW ANYTHING OF IT.
>> YEAH, I DON'T KNOW.
>> WE HAVE STUMPED THE SPEAKERS
HERE.
OKAY.
WELL, THERE'S YET ANOTHER ONE.
THAT JUST CAME IN.
WHAT ABOUT THE MECHANISM OF
PARKINSON PLUS SYNDROMES, LIKE
PSP, CBD?
>> YEAH, SO CORTICOBASAL
SYNDROME, PROGRESS OF
SUPERNUCLEAR PALSY, MULTIPLE
CYST TOM ATROPHY AND OTHER
SYNUCLEINOPATHY.
THESE TEND TO HAVE DIFFERENT
PATHOLOGIES.
MSA IS A SYNUCLEINOPATHY LIKE
PARKINSON'S DISEASE BUT IT
ACCUMULATES NOT IN NEURONS BUT
IN GLIA.
PROGRESSIVE SUPERVISORNUCLEAR SR
NUCLEAR PALSY IS A TAUOPATHY.
WE'RE ANALYZING ALL OF THESE TO
LOOK FOR COMMONALITIES AND
DIFFERENCES IN THEIR GENETIC
ARCHITECTURE.
PART OF THEIR CHALLENGE IS
THEY'RE VERY, VERY RARE SO IT'S
HARD TO COLLECT ENOUGH SAMPLES
TO MAKE GOOD GENETIC INFERENCES.
BUT CERTAINLY UNDERSTANDING
WHAT'S DIFFERENT AND THE LIKE
BETWEEN ALL OF THESE DEEDS, I
THINK IS A CENTRAL AIM OF WHAT
WE'RE TRYING TO DO.
>> ALL RIGHT.
WELL, LET'S SEE.
ARE THERE ANY OTHER QUESTIONS
HERE?
I GUESS NOT, SO WE'RE ACTUALLY
JUST A LITTLE BIT AHEAD OF 6:00,
BUT I THINK THAT WE'LL CALL TO A
CLOSE.
THANK YOU GUYS VERY, VERY MUCH.
THIS WAS REALLY SPECTACULAR.
[APPLAUSE]
SO ANYWAY.
WE REALLY APPRECIATE IT.
>> THANK YOU.