Functional Analysis of α-Synuclein in Ectopic Neuronal Cell Cycle Re-Entry

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 DESCRIPTION (provided by applicant): α-Synuclein (α-Syn) is a 140-amino acid presynaptic protein whose normal function remains poorly understood (Bendor et al., 2013). Histological staining of α-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 α-Syn is responsible for a subset of these neurodegenerative disorders appropriately referred to as Synucleinopathies (Spillantini and Goedert, 2000). However, the mechanism(s) of α-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 α-Syn toxicity is essential to identify alternative therapeutic approaches. Duplication or triplication of the gee that encodes α-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 α-Syn becomes toxic through the formation of oligomers and fibrils. Extracellular application of preformed α-Syn oligomers or fibrils induces neuronal dysfunction and subsequent degeneration, with the oligomers demonstrating the greatest cytotoxicity. One potential mechanism for α-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 α-Syn in neuronal CCR remains virtually unknown. Thus, using various models of AD and PD, the hypothesis that α-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 α-Syn in neurodegenerative diseases.