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From human genetics to therapeutic hypothesis for nervous system disorders: pain and Alzheimer’s disease

Air date: Wednesday, November 8, 2017, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
Description: NIH Director's Wednesday Afternoon Lecture Series

Human genetics can reveal potential drug targets for the treatment of both chronic pain and Alzheimer's disease, two diverse yet unrelated nervous system disorders. Chronic pain disrupts the lives of many people and represents a major burden on society. New pain therapies are needed because current treatments for severe musculoskeletal pain and neuropathic pain are often lacking in efficacy and/or disadvantaged by side effects and the potential for abuse. The Nav1.7 voltage-gated sodium channel is mutated in humans who are completely insensitive to pain, and is required for pain sensory signaling in mice. Small-molecule inhibitors selective for Nav1.7 have analgesic activity in animal models and might have therapeutic potential in humans.

Alzheimer's disease (AD) afflicts five million people in the U.S. and millions more globally. Human genetics can provide important insights into the molecular and cellular pathogenesis of AD, which remain poorly understood. Loss-of-function genetic variants in TREM2 (Triggering Receptor Expressed on Myeloid cells 2) greatly increase the risk of AD-about a three--fold increase in risk, which is on a par with the largest AD genetic risk factor, apolipoprotein E4 (APOE4). TREM2 is specifically expressed in myeloid cells and only by microglia in the brain--implicating innate immunity mechanisms in the pathogenesis of AD. TREM2 interacts biochemically and functionally with two other major AD risk genes, APOE and APOJ (which encode apolipoproteins), and TREM2 is required for the normal ability of microglia to engulf amyloid-beta aggregates and respond to amyloid plaque.

Dr. Sheng is Vice-President, Neuroscience, and responsible for directing neuroscience research and drug discovery efforts at Genentech. An expert on synapse biology, Dr. Sheng is now focused on the genetic underpinnings and pathogenic mechanisms of neurodegenerative disease, including Alzheimer’s, Parkinson’s, fronto-temporal dementia. In this translational context, recent research activities of the Sheng lab have centered on the molecular and cellular mechanisms of synapse loss, regulation of mitophagy, microglial involvement in neurodegeneration, and functions of TREM2.

For more information go to https://oir.nih.gov/wals/2017-2018/human-genetics-therapeutic-hypothesis-nervous-system-disorders-pain
Author: Morgan Sheng, MBBS, Ph.D., Vice President, Neuroscience, Genetech, Inc.
Runtime: 1 hour