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，仅在北美就影响超过100万人，并导致生活质量和功能能力的潜在降低。PD的标志是由蛋白质α-突触核蛋白组成的神经元细胞质内含物的脑积聚，但在一系列神经退行性疾病（包括路易体痴呆）中观察到α-突触核蛋白脑聚集体的存在。一些研究结果表明，α-突触核蛋白淀粉样蛋白病理学可能通过蛋白质构象机制的自模板改变在疾病进展期间传播，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-突触核蛋白病理学的进展。从治疗方面来看，确定α-突触核蛋白聚集在疾病中传播的相对重要性、机制和生理后果至关重要。在该提案中，提出了两个主要的具体目标来为α-突触核蛋白诱导和疾病传播提供信息：1）使用野生型和致病突变形式 α-突触核蛋白具有独特的聚集特性，我们将直接研究α-突触核蛋白聚集体可以在中枢神经系统内扩散，并以特定的构象特征从外周扩散。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、神经元中间丝的完整性、神经毒性和外源性α-突触核蛋白激发引起的α-突触核蛋白病理学诱导和传播中的年龄相关变化。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，旨在指导新型治疗方法的开发。

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.