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

 描述（由申请人提供）：α-突触核蛋白（α-Syn）是一种140个氨基酸的突触前蛋白，其正常功能仍然知之甚少（Bendor等人，2013年）。α-Syn的组织学染色表明，蛋白质的错误折叠纤维是Lewy的主要成分 在患有帕金森病（PD）和包括阿尔茨海默病（AD）在内的其他神经退行性疾病的患者的大脑中发现的LB包涵体。事实上，人们普遍认为α-Syn的聚集是这些神经退行性疾病的一个子集的原因，适当地称为突触核蛋白病（Spillantini和Goedert，2000）。然而，α-Syn毒性的机制及其在AD中的确切作用仍然未知。尽管在对抗AD和PD方面做出了值得称赞的努力，但迄今为止所做的任何尝试都没有成功阻止或预防疾病进展。因此，更好地了解α-Syn毒性对于确定替代治疗方法至关重要。 编码α-Syn的gee的重复或三重或蛋白质中的点突变（A53 T、A30 P、E46 K）对于早发性PD是完全渗透性的。流行的理论是α-Syn的突变或积累通过形成寡聚体和原纤维而变得有毒。预先形成的α-Syn寡聚体或原纤维的细胞外应用诱导神经元功能障碍和随后的变性，其中寡聚体表现出最大的细胞毒性。 α-Syn毒性的一种潜在机制涉及PD中未被充分认识的事件，异位细胞周期再进入（CCR）（Wang等人，2009），其中静止的神经元重新进入细胞周期并最终死亡。然而，α-Syn在神经元CCR中的功能作用几乎仍然未知。因此，使用AD和PD的各种模型，将检验α-Syn通过保守的tau依赖性机制调节CCR的假设。 这些实验的结果和产生的工具将有助于药物发现工作和未来对α-Syn在神经退行性疾病中作用的研究。

 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.