Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct “strains” having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.

中文翻译：

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突触核蛋白病的神经病理学和分子诊断

突触核蛋白病是临床和病理学上的异质性疾病，其特征在于神经元和神经胶质细胞中 α-突触核蛋白以路易体、路易神经突、神经元细胞质内含物和神经胶质细胞质内含物的形式病理性聚集。突触核蛋白病可分为两种主要疾病实体：路易体病和多系统萎缩症（MSA）。路易体病常见的临床表现有帕金森病（PD）、PD伴痴呆和路易体痴呆（DLB），而MSA有两种主要的临床亚型，以小脑性共济失调为主的MSA和以帕金森症为主的MSA。目前还没有针对突触核蛋白病的疾病缓解疗法，但从探索 α-突触核蛋白转化为病理性寡聚体和不溶性原纤维的机制的分子遗传学和模型中获得的信息为最终治疗带来了希望。目前尚不清楚α-突触核蛋白如何与不同的细胞病理学（例如路易体和神经胶质细胞质内含物）相关，以及哪些因素决定神经解剖学和细胞类型的脆弱性。体外和体内实验积累的证据表明，源自路易体病和 MSA 的 α-突触核蛋白种类是具有不同播种特性的不同“菌株”。体外接种测定的最新进展，例如实时震动诱导转化 (RT-QuIC) 和蛋白质错误折叠循环扩增 (PMCA)，不仅证明了突触核蛋白病中独特的接种活性，而且还为利用易于获取的外周组织样本。对源自重组或脑源丝的 α-突触核蛋白的低温电子显微镜 (cryo-EM) 结构研究为突触核蛋白病的播种机制提供了新的见解。在这篇综述中，我们描述了突触核蛋白病的临床、遗传和神经病理学特征，包括对路易体病分类和分期演变的讨论。我们还简要讨论了路易体形成的拟议机制，以及支持路易体病和 MSA 中存在不同 α-突触核蛋白菌株的证据。