Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson's Disease.

Abstract

Parkinson's disease (PD) involves progressive dopaminergic neuron degeneration and motor deficits. Oligodendrocyte dysfunction contributes to PD pathogenesis through impaired myelination.Single-nucleus RNA sequencing (snRNA-seq) of PD mice revealed compromised oligodendrocyte differentiation anddownregulation. Pseudotemporal trajectory analysis via Monocle2 demonstrated impaired oligodendrocyte maturation in PD oligodendrocytes, correlating with reduced myelin-related gene expression (,,,,,). DoRothEA-predicted regulon activity identified STAT5B as a key transcriptional regulator.Oligodendrocyte-specificactivation improved myelin integrity, as validated by Luxol Fast Blue staining and transmission electron microscopy; attenuated dopaminergic neuron loss; and improved motor function. Mechanistically,binds thepromoter to drive transcription, a finding confirmed by the luciferase assay, while the DNMT3A-mediated hypermethylation of thepromoter epigenetically silences its expression, as verified by MethylTarget sequencing and methylation-specific PCR.DNMT3A inhibited the expression ofby affecting its methylation, which reduced the transcription of, caused oligodendrocyte myelin damage, and eventually led to dopamine neuron damage and motor dysfunction in an MPTP-induced mouse model. This DNMT3A--axis underlies PD-associated myelin damage, connecting epigenetic dysregulation with oligodendrocyte dysfunction and subsequent PD pathogenesis.