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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2025-07-01
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| author | Yibo Li Zhaowen Su Jitong Zhai Qing Liu Hongfang Wang Jiaxin Hao Xiaofeng Tian Jiamin Gao Dandan Geng Lei Wang |
| author_facet | Yibo Li Zhaowen Su Jitong Zhai Qing Liu Hongfang Wang Jiaxin Hao Xiaofeng Tian Jiamin Gao Dandan Geng Lei Wang |
| author_sort | Yibo Li |
| collection | DOAJ |
| description | <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. |
| format | Article |
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| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-19092acaba4e494bb4baf03e5fb4ac572025-08-20T03:36:39ZengMDPI AGCells2073-44092025-07-011415114510.3390/cells14151145Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson’s DiseaseYibo Li0Zhaowen Su1Jitong Zhai2Qing Liu3Hongfang Wang4Jiaxin Hao5Xiaofeng Tian6Jiamin Gao7Dandan Geng8Lei Wang9Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaThe Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, ChinaDepartment of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, China<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.https://www.mdpi.com/2073-4409/14/15/1145Parkinson’s diseaseoligodendrocytesubstantia nigrasingle-nuclear RNA sequencingmyelin sheathmethylation |
| spellingShingle | Yibo Li Zhaowen Su Jitong Zhai Qing Liu Hongfang Wang Jiaxin Hao Xiaofeng Tian Jiamin Gao Dandan Geng Lei Wang Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson’s Disease Cells Parkinson’s disease oligodendrocyte substantia nigra single-nuclear RNA sequencing myelin sheath methylation |
| title | Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson’s Disease |
| title_full | Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson’s Disease |
| title_fullStr | Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson’s Disease |
| title_full_unstemmed | Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson’s Disease |
| title_short | Oligodendrocyte-Specific STAT5B Overexpression Ameliorates Myelin Impairment in Experimental Models of Parkinson’s Disease |
| title_sort | oligodendrocyte specific stat5b overexpression ameliorates myelin impairment in experimental models of parkinson s disease |
| topic | Parkinson’s disease oligodendrocyte substantia nigra single-nuclear RNA sequencing myelin sheath methylation |
| url | https://www.mdpi.com/2073-4409/14/15/1145 |
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