Mechanisms of Aggregated Alpha-Synuclein Induction and Progression

描述（由申请人提供）：帕金森病（PD）是最常见的运动障碍，仅在北美就有超过100万人受到影响，并导致生活质量和功能能力的潜在降低。PD的一个特征是由α突触核蛋白组成的神经元胞质包涵体在脑内积聚，但在包括路易体痴呆在内的一系列神经退行性疾病中也观察到α突触核蛋白脑聚集物的存在。一些研究结果表明，α -突触核蛋白淀粉样蛋白病理可能通过蛋白质构象机制的自模板改变在疾病进展过程中扩散，然而其他替代和/或协同生物学机制，如我们的数据所支持的，也可能导致α -突触核蛋白病理进展。从治疗角度来看，确定α突触核蛋白聚集在疾病中扩散的相对重要性、机制和生理后果是至关重要的。在这一提议中，我们提出了两个主要的具体目的来了解α突触核蛋白诱导和疾病传播的信息：1)使用具有独特聚集特性的α突触核蛋白野生型和致病突变型，我们将直接研究α突触核蛋白聚集可以在中枢神经系统内传播，也可以从具有特定构象特征的外周传播。2)我们将评估其他生物机制的重要性，包括蛋白质网络稳态的扰动、神经元中间丝完整性、神经毒性和外源性α突触核蛋白挑战诱导和传播α突触核蛋白病理的年龄相关变化。这些研究将为PD疾病进展中α突触核蛋白聚集的机制和参与提供重要见解，目的是指导新疗法的发展。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is the most common movement disorder affecting over one million people in North America alone and results in an insidious reduction in the quality of life and ability to function. A hallmark of PD is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein alpha synuclein, but the presence of alpha synuclein brain aggregates is observed in a spectrum of neurodegenerative diseases, including dementia with Lewy body. Several findings suggest that alpha synuclein amyloid pathology may spread during disease progression by a self-templating alteration in protein conformation mechanism, however other alternative and/or synergistic biological mechanisms, as supported by our data, could also lead to progression of alpha synuclein pathology. From a therapeutic aspect it is critical to determine the relative importance, mechanisms and physiological consequences of the spread of alpha synuclein aggregation in disease. It this proposal, two major specific aims are proposed to inform on alpha synuclein induced and spread of disease: 1) Using both wild-type and disease causing mutant forms of alpha synuclein with unique aggregation properties, we will directly investigated that alpha synuclein aggregation can spread within the central nervous system and from the periphery with specific conformational characteristics. 2) We will assess the importance of alternative biological mechanisms including perturbation of the protein network homeostasis, neuronal intermediate filament integrity, neurotoxicity and age-related changes in the induction and propagation of alpha synuclein pathology by exogenous alpha synuclein challenges. These studies will provide critical insights on the mechanisms and the involvement of alpha synuclein aggregation in PD disease progression with the objective of guiding the development of novel therapeutics.