Pathogenesis and Diagnosis of Multiple System Atrophy

多系统萎缩(MSA)是一种进行性、退行性的神经系统疾病， 以不同程度的帕金森症、自主神经功能障碍和小脑功能受损为临床特征。MSA的主要病理特征是少突胶质细胞中存在胶质细胞质内含物(GCIS)。在新生的MSA研究方面，最近的重大进展是制定了MSA临床诊断的共识标准，并发现GCIS的主要成分是α-突触核蛋白。MSA的研究一直受到以下事实的阻碍：MSA虽然并不罕见，但还不够普遍，以至于一个中心不能研究足够数量的受试者，直到 现在，对参与这种疾病的分子缺乏洞察力。 拟议工作的重点是研究MSA的致病因素，特别是α-突触核蛋白所起的作用，并评估和完善用于诊断和跟踪疾病过程的临床和实验室评估。我们努力的一个中心组成部分将是招募175名临床可能的MSA受试者和评估350名病例对照受试者的队列，并每半年进行一次评估。临床评估将在11个地点进行，并由核心A(行政和临床)和核心B(数据)监督。这组MSA和对照受试者将成为环境风险因素研究(项目1)的基础，以及核心C(神经病理学)开发脑库和核心D(遗传学)开发DNA存储库的基础。MSA受试者中的一个小组将参与#年自主神经功能的研究 MSA(项目4)。项目2和项目3将研究在Core C中获得的MSA受试者大脑中a-突触核蛋白的生物学。项目3将利用过表达g-突触核蛋白的转基因小鼠来研究影响a-突触核蛋白在少突胶质细胞中积累、聚集和毒性的因素。提出的计划项目是第一个全面研究MSA的诊断工具和发病机制。

Multiple system atrophy (MSA) is a progressive, degenerative neurological disorder, which is characterized clinically by the combination of varying degrees of Parkinsonism, autonomic dysfunction and impaired cerebellar function. The cardinal pathological feature of MSA is the presence of glial cytoplasmic inclusions (GCIs) in oligodendrocytes. Significant recent developments in the nascent research of MSA have been the development of consensus criteria for the clinical diagnosis of MSA and the discovery that a major component of GCIs is a-synuclein. Research in MSA has been hampered by the fact that MSA, though not rare, is not common enough for a single center to study a sufficient number of subjects and, until now, an absence of insights into molecules involved in the disorder. The focuses of the proposed work are to study pathogenic factors for MSA, particularly the role that alpha-synuclein plays, and to evaluate and refine clinical and laboratory assessments used to diagnose and follow the course of the illness. A central component of our effort will be recruitment and semiannual evaluation of a cohort of 175 clinically probable MSA subjects and evaluation 350 case control subjects. The clinical evaluations will be carried out at 11 sites and overseen by Core A (Administrative and Clinical) and Core B (Data). These groups of MSA and control subjects will be the basis for studies of environmental risk factors (Project 1) and the development of a brain bank by Core C (Neuropathology) and a DNA Repository by Core D (Genetics). A subgroup of the MSA subjects will be involved in studies of autonomic function in MSA (Project 4). Projects 2 and 3 will study the biology of a-synuclein in brains from MSA subjects acquired in Core C. Project 3 will utilize transgenic mice that overexpress g-synuclein to study factors that affect accumulation, aggregation and toxicity of a-synuclein in oligodendrocytes. The proposed program project is the first comprehensive study of a diagnostic tools and pathogenesis of MSA.