MECHANISIMS OF SYNUCLEIN PATHOGENESIS IN MSA

神经细胞或神经胶质细胞内异常堆积的丝状聚集物是神经病理。 是许多散发性和遗传性神经退行性疾病的特征。例如，神经元中由细丝状α-突触核蛋白(a-syn)聚集体形成的路易体(Lbs)是帕金森病(PD)、痴呆症(DBS)和阿尔茨海默病(AD)亚型的特征，被称为AD的LBVAD(LBVAD)，而由a-SYN细丝组成的胶质细胞质包涵体(GCIS)是多系统萎缩(MSA)的标志性病变。Gcis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帕金森病，即a-syn。 是LBS和GCIS主要成分，突变体和野生型a-syn在体外形成与LBS和GCIS相似的细丝。此外，还发现β-(b-syn)和γ-突触核蛋白(g-syn)在营养不良过程中积聚，a-syn在MSA的GCI以及所有突触核病的a-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，氧化/硝化损伤在糖尿病的发生/发展中起着重要作用。 MSA。为了在MSA中专门验证这一假设，本项目的AIMS 1-4将分析氧化/硝化损伤在a-syn细丝形成和a-syn纤维聚集到GCIS中的潜在贡献。此外，AIMS 5和6将决定GCIS是否/如何影响受影响的神经胶质细胞的活性。深入了解突触核蛋白病理的潜在机制以及它们如何导致脑变性，可能会改进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.