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

 描述(申请人提供)：α-突触核蛋白(α-Syn)是一种由140个氨基酸组成的突触前蛋白，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，错误折叠的蛋白质纤维是路易的主要成分 在患有帕金森氏病(PD)和其他神经退行性疾病(包括阿尔茨海默病(AD))的患者的大脑中发现的身体(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，适当地称为联核病(Spillantini and Goedert，2000)。然而，α-Syn毒性的机制(S)及其在AD中的确切作用仍不清楚。尽管抗击阿尔茨海默病和帕金森病的努力值得称赞，但迄今为止在阻止或防止疾病进展方面所做的努力都没有成功。因此，更好地了解α-SYN的毒性对于确定替代治疗方法是至关重要的。编码α-Syn的GEE或蛋白质点突变(A53T、A30P、E46K)的重复或三倍对早发性帕金森病是完全穿透的。流行的理论是，α-syn的突变或积累通过形成寡聚体和纤维而变得有毒。细胞外应用预先形成的α-syn寡聚体或纤维会导致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毒性的一个潜在机制涉及PD中一个被低估的事件，异位细胞周期重新进入(Ccr)(Wang等人，2009年)，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中的功能仍不清楚。因此，使用AD和PD的各种模型，将检验α-Syn通过保守的tau依赖机制调控Ccr的假设。这些实验的结果，以及产生的工具，将有助于药物发现努力和未来对α-Syn在神经退行性疾病中的作用的研究。

 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.