Transcriptional Dysregulation in the Cerebellum Triggered by Oligodendroglial α-synucleinopathy: Insights from a Transgenic Mouse into the Early Disease Mechanisms of MSA

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by abnormal accumulation of α-synuclein, progressive neuronal loss, motor impairment and widespread pathological changes, which include significant involvement of the cerebellum. To understand the early molecular mechanisms that might underlie α-synuclein-triggered MSA cerebellar pathology, we performed RNA sequencing (RNA-Seq) of cerebellar samples from a well-established model of MSA. RNA-Seq and differential gene expression analysis was conducted in the PLP-αSyn model of MSA. Cerebellum from two and 12-month-old MSA and wildtype mice were used. Gene ontology (GO) and KEGG enrichment analyses of the differentially expressed genes (DEGs) were performed to explore processes involved in MSA-like disease progression. The overlap between transcriptional changes in MSA and those associated with aging was also evaluated. RNA-Seq analysis demonstrated significant transcriptional dysregulation in cerebellum from MSA mice, even at early stages. GO and KEGG analyses of DEGs point to a potential role of synaptic dysfunction, cellular signaling dysregulation and inflammation in the cerebellar pathology of MSA mice. In addition, those changes exacerbate with disease progression. Additionally, our analysis of aging in both control and PLP-αSyn mice showed that age-related transcriptional changes in mid-aged controls seem to be present in young MSA mice. Thus, MSA-like pathology might lead to an acceleration of aging-related mechanisms. Our findings demonstrate significant cerebellar transcriptional dysregulation triggered by oligodendroglial α-synucleinopathy in PLP-αSyn mice, revealing pathways that might be critical for the early cerebellar pathology of MSA, and that may serve as potential molecular targets for therapeutic interventions in this devastating disorder.