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α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。一些发现表明，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。根据这一建议，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情况：1)利用具有独特聚集特性的野生型和致病突变形式的α突触核蛋白，我们将直接研究具有特定构象特征的α突触核蛋白聚集可以在中枢神经系统内和从外周扩散。2)我们将评估替代生物学机制的重要性，包括蛋白质网络稳态的扰动、神经元中间丝完整性、神经毒性以及外源性α突触核蛋白攻击在诱导和繁殖α突触核蛋白病理过程中与年龄相关的变化。这些研究将对阿尔法突触核蛋白聚集在帕金森病进展中的机制和参与提供重要的见解，目的是指导新疗法的开发。

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 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.