Parkinson's disease (PD) imposes a major burden on our aging population, and represents a neurodegenerative disorder that affects broad areas of the brain, but primarily manifests as a loss of dopaminergic neurons in the Substantia nigra. ?-Synuclein is thought to play a central role in PD because ?- synuclein mutations and polymorphisms are linked to PD, and because ?-synuclein containing inclusion bodies (Lewy bodies) are found neuropathologically in PD. Current data suggest that ?-synuclein promotes neurodegeneration in PD by misfolding into a toxic conformation, most likely as a microaggregate, that is deleterious to the neurons harboring the toxic ?-synuclein conformer. However, the mechanisms mediating the toxic effects of ?-synuclein remain incompletely understood. The present project proposes to investigate the mechanisms underlying ?-synuclein neurotoxicity in two specific aims, using cultured human neurons and mouse brains in situ as model systems, and focusing in particular on an understanding of the nature of ?- synuclein toxicity. The project will utilize an interdisciplinary approach with a particular emphasis on electrophysiological recordings to probe the relation of neuronal function, in particular as regards synaptic transmission, to ?-synuclein neurotoxicity. The results from these experiments will elucidate the extent and nature of ?-synuclein neurotoxicity in mouse and in human neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS094733-05
Application #
9744825
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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