?-Synuclein (?-Syn) is a 140-amino acid presynaptic protein whose normal function remains poorly understood (Bendor et al., 2013). Histological staining of ?-Syn indicate that misfolded fibrils of the protein are the primary component of Lewy body (LB) inclusions found in the brains of patients afflicted with Parkinson's Disease (PD) and other neurodegenerative orders including Alzheimer's disease (AD). In fact, it is widely accepted that the aggregation of ?-Syn is responsible for a subset of these neurodegenerative disorders appropriately referred to as Synucleinopathies (Spillantini and Goedert, 2000). However, the mechanism(s) of ?-Syn toxicity, and its precise role in AD, remain unknown. Despite laudable efforts to combat AD and PD, none of the attempts made to date have been successful at halting or preventing disease progression. Therefore, a greater understanding of ?-Syn toxicity is essential to identify alternative therapeutic approaches. Duplication or triplication of the gee that encodes ?-Syn or point mutations in the protein (A53T, A30P, E46K) is fully penetrant for early-onset PD. The prevailing theory is that mutation or accumulation of ?-Syn becomes toxic through the formation of oligomers and fibrils. Extracellular application of preformed ?-Syn oligomers or fibrils induces neuronal dysfunction and subsequent degeneration, with the oligomers demonstrating the greatest cytotoxicity. One potential mechanism for ?-Syn toxicity involves an underappreciated event in PD, ectopic cell cycle re-entry (CCR) (Wang et al., 2009), where quiescent neurons re-enter the cell cycle and eventually die. However, the functional role of ?-Syn in neuronal CCR remains virtually unknown. Thus, using various models of AD and PD, the hypothesis that ?-Syn modulates CCR through a conserved tau-dependent mechanism will be tested. The results from these experiments, and the tools that are generated, will aid drug discovery efforts and future investigations on the role of ?-Syn in neurodegenerative diseases.

Public Health Relevance

Completion of the project will provide new information about the ?-synuclein protein that is mutated in Parkinson's disease (PD), and implicated in Alzheimer's disease (AD), both for which there is no current treatment or cure. The new models that are generated will be instrumental for the eventual development of therapeutic strategies that target ?-synuclein toxicity or aberrant cell-cycle protein expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS092444-02
Application #
9181324
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sutherland, Margaret L
Project Start
2016-01-01
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Norambuena, Andrés; Wallrabe, Horst; McMahon, Lloyd et al. (2017) mTOR and neuronal cell cycle reentry: How impaired brain insulin signaling promotes Alzheimer's disease. Alzheimers Dement 13:152-167
Khan, Shahzad S; Bloom, George S (2016) Tau: The Center of a Signaling Nexus in Alzheimer's Disease. Front Neurosci 10:31