MECHANISIMS OF SYNUCLEIN PATHOGENESIS IN MSA

神经元或神经胶质中丝状聚集物的异常积聚是神经病理学的 许多散发性和遗传性神经退行性疾病的标志。例如，由神经元中的丝状α-突触核蛋白（α-syn）聚集体形成的路易体（LB）是帕金森病（PD）、具有LB的痴呆（DLB）和被称为AD的LB变体（LBVAD）的阿尔茨海默病（AD）亚型的特征，而由α-syn细丝组成的神经胶质细胞质内含物（GCI）是多系统萎缩（MSA）的标志性病变。GCI和LBs在神经退行性疾病中发挥作用的假设一直受到怀疑，直到有证据表明a-syn基因突变导致家族性PD，a-syn基因突变导致家族性PD。 是LB和GCI主要组分，且突变体和野生型α-syn在体外形成与LB和GCI中的那些相似的细丝。此外，还表明β-（b-syn）和γ-突触核蛋白（g-syn）在营养不良过程中积累，并且α-syn在MSA的GCI以及所有突触核蛋白病的α-syn病变中被选择性硝化。因此，我们假设丝状a-syn聚集体的积累部分是由氧化/硝化损伤诱导的，所述氧化/硝化损伤在以下疾病的发生/进展中起重要作用： MSA。为了特别在MSA中检验这一假设，本项目的目标1-4将分析氧化/硝化损伤在a-syn细丝形成和a-syn原纤维聚集成GCI中的潜在贡献。此外，目标5和6将确定GCI是否/如何损害受影响神经胶质细胞的活力。深入了解突触核蛋白病理学的潜在机制以及它们如何促进脑变性，可能会改善MSA的诊断和治疗策略。

Abnormal accumulations of filamentous aggregates in neurons or glia are neuropathological hallmarks of many sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) formed by filamentous alpha-synuclein (a-syn) aggregates in neurons are characteristic of Parkinson's disease (PD), dementia with LBs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while glial cytoplasmic inclusions (GCIs) composed of a-syn filaments are signature lesions of multiple system atrophy (MSA). The hypothesis that GCIs and LBs play a role in neurodegenerative disease was viewed with skepticism until it was shown that mutations in the a-syn gene cause familial PD, that a-syn is a major component of LBs and GCIs, and that mutant and wild type a-syn form filaments in vitro similar to those in LBs and GCIs. Moreover, it also was shown that beta- (b-syn) and gamma-synucleins (g-syn) accumulate in dystrophic processes, and that a-syn is selectively nitrated in GCIs of MSA as well as in a-syn lesions of all synucleinopathies. Thus, we hypothesize that the accumulations of filamentous a-syn aggregates are induced in part by oxidative/nitrative damage that plays an important role in the onset/progression of MSA. To test this hypothesis specifically in MSA, Aims 1-4 of this Project will analyze the potential contribution of oxidative/nitrative damage in a-syn filament formation and a-syn fibril aggregation into GCIs. In addition, Aims 5 and 6 will determine if/how GCIs compromise the viability of affected glial cells. Insights into the underlying mechanisms of synuclein pathologies and how they contribute to brain degeneration may lead to improved strategies for the diagnosis and treatment of MSA.