Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by autonomic failure and motor impairment. The hallmark pathologic finding in MSA is widespread oligodendroglial cytoplasmic inclusions rich in aggregated α-synuclein (αSyn). MSA is widely held to be an oligodendroglial synucleinopathy, and we outline lines of evidence to support this assertion, including the presence of early myelin loss. We consider emerging data that support the possibility of neuronal or immune dysfunction as primary drivers of MSA. These hypotheses are placed in the context of a major recent discovery that αSyn is conformationally distinct in MSA versus other synucleinopathies such as Parkinson's disease. We outline emerging techniques in epidemiology, genetics, and molecular pathology that will shed more light on this mysterious disease. We anticipate a future in which cutting-edge developments in personalized disease modeling, including with pluripotent stem cells, bridge mechanistic developments at the bench and real benefits at the bedside.

中文翻译：

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多系统萎缩：病理学、发病机制和前进道路


多系统萎缩 （MSA） 是一种致命的神经退行性疾病，其特征是自主神经衰竭和运动障碍。MSA 的标志性病理发现是广泛的少突胶质细胞质包涵体，富含聚集的 α-突触核蛋白 （αSyn）。MSA 被广泛认为是一种少突胶质细胞突触核蛋白病，我们概述了支持这一断言的证据，包括存在早期髓鞘丢失。我们认为支持神经元或免疫功能障碍可能性的新数据是 MSA 的主要驱动因素。这些假设被置于最近的一项重大发现的背景下，即 αSyn 在 MSA 中与其他突触核蛋白病（如帕金森病）在构象上是不同的。我们概述了流行病学、遗传学和分子病理学方面的新兴技术，这些技术将更多地阐明这种神秘疾病。我们预计未来个性化疾病建模的前沿发展，包括多能干细胞，将实验室的机制发展与床旁的真正益处联系起来。