Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy

Synucleinopathies are composed of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Alpha-synuclein (alpha-Syn) forms aggregates mainly in neurons in PD and DLB, while oligodendroglial alpha-Syn aggregates are characteristic of MSA. Recent studies have demonstrated that injections of synthetic alpha-Syn preformed fibrils (PFFs) into the brains of wild-type (WT) animals induce intraneuronal alpha-Syn aggregates and the subsequent interneuronal transmission of alpha-Syn aggregates. However, injections of alpha-Syn PFFs or even brain lysates of patients with MSA have not been reported to induce oligodendroglial alpha-Syn aggregates, raising questions about the pathogenesis of oligodendroglial alpha-Syn aggregates in MSA. Here, we report that WT mice injected with mouse alpha-Syn (m-alpha-Syn) PFFs develop neuronal alpha-Syn pathology after short postinjection (PI) intervals on the scale of weeks, while oligodendroglial alpha-Syn pathology emerges after longer PI intervals of several months. Abundant oligodendroglial alpha-Syn pathology in white matter at later time points is reminiscent of MSA. Furthermore, comparison between young and aged mice injected with m-alpha-Syn PFFs revealed that PI intervals rather than aging correlate with oligodendroglial alpha-Syn aggregation. These results provide novel insights into the pathological mechanisms of oligodendroglial alpha-Syn aggregation in MSA.