Oligodendroglial α-Synucleinopathy Remodels Transcriptional Programs Associated with Nigral Vulnerability in Experimental Multiple System Atrophy

Abstract Multiple system atrophy (MSA) is characterized by oligodendroglial α-synucleinopathy and selective degeneration of striatonigral and olivopontocerebellar systems, but the molecular events associated with regional vulnerability remain incompletely understood. Here, using the PLP-αSyn mouse model of MSA, which shows progressive striatonigral degeneration and later cerebellar involvement, we investigated whether oligodendroglial α-synucleinopathy is accompanied by transcriptional changes in the ventral midbrain before overt nigral neurodegeneration and whether related signatures follow the regional pattern of disease progression. We performed bulk RNA sequencing of ventral midbrain tissue, including substantia nigra, from PLP-αSyn mice and wildtype controls at 2 and 12 months of age. At 2 months, before overt dopaminergic neuronal loss, PLP-αSyn mice already showed marked ventral midbrain dysregulation, with increased RNA-processing and synaptic programs together with reduced mitochondrial, metabolic and myelin-related pathways. At 12 months, these alterations persisted and were accompanied by stronger suppression of oxidative phosphorylation, mitochondrial inner membrane and respiratory-chain complexes, fatty-acid/lipid metabolism and myelin maintenance. Cross-regional comparison with cerebellar transcriptomic data from the same model revealed that mitochondrial and myelin-related impairments emerged earlier and more strongly in the ventral midbrain than in the cerebellum, where related signatures became more evident at later disease stages. These findings identify early and progressive transcriptional dysregulation of bioenergetic, metabolic and oligodendroglial/myelin-support programs in experimental MSA and highlight these processes as candidate contributors to regional vulnerability in this model.