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

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

<b>Background:</b> Parkinson’s disease (PD) involves progressive dopaminergic neuron degeneration and motor deficits. Oligodendrocyte dysfunction contributes to PD pathogenesis through impaired myelination. <b>Methods:</b> Single-nucleus RNA sequencing (snRNA-seq) of PD mice...

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Main Authors: Yibo Li, Zhaowen Su, Jitong Zhai, Qing Liu, Hongfang Wang, Jiaxin Hao, Xiaofeng Tian, Jiamin Gao, Dandan Geng, Lei Wang
Format: Article
Language:English
Published: MDPI AG 2025-07-01
Series:Cells
Subjects:
Parkinson’s disease
oligodendrocyte
substantia nigra
single-nuclear RNA sequencing
myelin sheath
methylation
Online Access:https://www.mdpi.com/2073-4409/14/15/1145
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Summary:<b>Background:</b> Parkinson’s disease (PD) involves progressive dopaminergic neuron degeneration and motor deficits. Oligodendrocyte dysfunction contributes to PD pathogenesis through impaired myelination. <b>Methods:</b> Single-nucleus RNA sequencing (snRNA-seq) of PD mice revealed compromised oligodendrocyte differentiation and <i>STAT5B</i> downregulation. Pseudotemporal trajectory analysis via Monocle2 demonstrated impaired oligodendrocyte maturation in PD oligodendrocytes, correlating with reduced myelin-related gene expression (<i>Sox10</i>, <i>Plp1</i>, <i>Mbp</i>, <i>Mog</i>, <i>Mag</i>, <i>Mobp</i>). DoRothEA-predicted regulon activity identified STAT5B as a key transcriptional regulator. <b>Results:</b> Oligodendrocyte-specific <i>STAT5B</i> activation improved myelin integrity, as validated by Luxol Fast Blue staining and transmission electron microscopy; attenuated dopaminergic neuron loss; and improved motor function. Mechanistically, <i>STAT5B</i> binds the <i>MBP</i> promoter to drive transcription, a finding confirmed by the luciferase assay, while the DNMT3A-mediated hypermethylation of the <i>STAT5B</i> promoter epigenetically silences its expression, as verified by MethylTarget sequencing and methylation-specific PCR. <b>Conclusions:</b> DNMT3A inhibited the expression of <i>STAT5B</i> by affecting its methylation, which reduced the transcription of <i>MBP</i>, caused oligodendrocyte myelin damage, and eventually led to dopamine neuron damage and motor dysfunction in an MPTP-induced mouse model. This DNMT3A-<i>STAT5B</i>-<i>MBP</i> axis underlies PD-associated myelin damage, connecting epigenetic dysregulation with oligodendrocyte dysfunction and subsequent PD pathogenesis.
ISSN:2073-4409

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