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的一个标志是由蛋白A -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。根据这一提议，提出了两个主要的具体目的：1)利用野生型和致病突变型的α-突触核蛋白

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.