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 #
5P50NS094733-04
Application #
9551091
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:
Burré, Jacqueline; Sharma, Manu; Südhof, Thomas C (2018) Cell Biology and Pathophysiology of ?-Synuclein. Cold Spring Harb Perspect Med 8:
Sheehan, Patricia; Yue, Zhenyu (2018) Deregulation of autophagy and vesicle trafficking in Parkinson's disease. Neurosci Lett :
Südhof, Thomas C (2017) Molecular Neuroscience in the 21st Century: A Personal Perspective. Neuron 96:536-541
Pan, Ping-Yue; Li, Xianting; Wang, Jing et al. (2017) Parkinson's Disease-Associated LRRK2 Hyperactive Kinase Mutant Disrupts Synaptic Vesicle Trafficking in Ventral Midbrain Neurons. J Neurosci 37:11366-11376
Giaime, Emilie; Tong, Youren; Wagner, Lisa K et al. (2017) Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice. Neuron 96:796-807.e6