Mechanisms of Aggregated Alpha-Synuclein Induction and Progression

描述(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100多万人受到影响，并导致生活质量和功能能力的潜伏下降。帕金森病的一个特征是大脑中由蛋白a-突触核蛋白组成的神经元胞浆内含物的积累，但在一系列神经退行性疾病中都可以观察到α-突触核蛋白脑聚集体的存在，包括路易体痴呆。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我模板改变在疾病进展过程中传播，然而，我们的数据支持的其他替代和/或协同生物学机制也可能导致α-突触核蛋白病理的进展。从治疗的角度来看，确定α-突触核蛋白聚集在疾病中扩散的相对重要性、机制和生理后果至关重要。在这一建议中，提出了两个主要的具体目的来告知α-突触核蛋白诱导和疾病的传播：1)同时使用野生型和引起疾病的突变形式的 α-突触核蛋白具有独特的聚集性质，我们将直接研究α-突触核蛋白聚集可以从中枢神经系统内扩散到具有特定构象特征的外周。2)我们将评估其他生物学机制的重要性，包括蛋白质网络的动态平衡、神经元中间丝完整性、神经毒性和年龄相关的变化在外源性α-突触核蛋白攻击诱导和繁殖α-突触核蛋白病理过程中的重要性。这些研究将对α-突触核蛋白聚集在PD疾病进展中的机制和参与提供重要的见解，目的是指导新的治疗方法的开发。

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 a-synuclein, but the presence of α-synuclein brain aggregates is observed in a spectrum of neurodegenerative diseases, including dementia with Lewy body. Several findings suggest that α-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 α-synuclein pathology. From a therapeutic aspect it is critical to determine the relative importance, mechanisms and physiological consequences of the spread of α-synuclein aggregation in disease. It this proposal, two major specific aims are proposed to inform on α-synuclein induced and spread of disease: 1) Using both wild-type and disease causing mutant forms of α-synuclein with unique aggregation properties, we will directly investigated that a-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 α-synuclein pathology by exogenous a-synuclein challenges. These studies will provide critical insights on the mechanisms and the involvement of α-synuclein aggregation in PD disease progression with the objective of guiding the development of novel therapeutics.