Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenous α-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains.

胶质细胞质内含物（GCI），通常被视为少突胶质细胞内的α-突触核蛋白（α-syn）阳性聚集体，是多系统萎缩的病理学标志。GCI中α-syn的起源尚不确定。在少突胶质细胞谱系细胞，少突胶质细胞前体细胞（OPC）和成熟少突胶质细胞（OLG）中几乎没有内源性α-syn表达的证据。在这里，基于体外通过使用原代大鼠细胞培养物进行的分析，我们阐明了重组人α-syn生成的预形成纤维（PFF）触发了多聚作用，OPCs中内源性α-syn激增，这归因于自噬蛋白水解不足。OPC的RNA序列分析表明，α-synPFF干扰了与神经调节和髓鞘形成有关的蛋白质的表达。此外，我们通过与PFF预孵育的OPC的分化来检测OLG中的胞质α-syn夹杂物。总体而言，我们的发现表明OPC中内源性α-syn积累的可能性可能会导致GCI的形成以及对多系统萎缩性大脑中神经元/神经胶质支持的扰动。