Pathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a “tropism” for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy.

由 α-突触核蛋白 (α-Syn) 的细胞内聚集体组成的病理学在各种神经退行性疾病中通过神经系统传播，包括帕金森病、路易体痴呆和多系统萎缩。发现结构上不同的 α-Syn 多晶型物，即所谓的菌株，支持了一种假设，即菌株特异性结构被模板化为由天然 α-Syn 形成的聚集体。假设这些不同的菌株决定了病理在组织中的扩散和聚集体的细胞影响，从而促成了临床表型的多样性。在这里，我们提供了由多系统萎缩相关少突胶质细胞蛋白 p25α 诱导的新型 α-Syn 菌株的证据。使用一系列生物物理、生化、细胞和体内分析，我们证明，与单独的 α-Syn 相比，亚化学计量浓度的 p25α 将 α-Syn 聚集重定向到具有不同结构和增强的体内促退性特性的独特 α-Syn/p25α 菌株中。α-Syn/p25α 菌株在人类多巴胺能神经元中诱导更大的内含物。体内,与 α-Syn PFF 相比，肌肉内注射 α-Syn/p25α 菌株的预制原纤维 (PFF) 导致人类 A53T 转基因（M83 系）小鼠大脑中包涵体病理学的缩短和解剖分布。对终末期小鼠脑干提取物中 α-Syn 聚集体的研究表明，基于 Förster 共振能量转移免疫分析和基于蛋白质错误折叠循环扩增测定，降低了 α-Syn 聚集体接种活性。当单侧注射到野生型小鼠的纹状体中时，α-Syn/p25α 菌株导致比 α-Syn PFF 更明显的运动表型，并且与 α-Syn PFF 相比表现出对黑质纹状体神经元的“趋向性”。全面的，