Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy
Abstract Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by parkinsonism, cerebellar dysfunction, and autonomic failure. Key pathological features of MSA include the formation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes (OLs), myelin loss, and neuroinflamma...
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BMC
2025-05-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-02014-y |
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| author | Sam Chi-Hao Liu Koping Chang Meng-Ling Chen Ming-Che Kuo Teh-Cheng Wang Ruey-Meei Wu |
| author_facet | Sam Chi-Hao Liu Koping Chang Meng-Ling Chen Ming-Che Kuo Teh-Cheng Wang Ruey-Meei Wu |
| author_sort | Sam Chi-Hao Liu |
| collection | DOAJ |
| description | Abstract Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by parkinsonism, cerebellar dysfunction, and autonomic failure. Key pathological features of MSA include the formation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes (OLs), myelin loss, and neuroinflammation. Although both inflammation and myelination are known to be critical in MSA, the roles of myelin proteins and their relationship with inflammation have often been overlooked. In this study, we injected AAV-Olig001 vectors carrying either human SNCA (AAV-hSNCA) or eGFP (AAV-eGFP) into the striatum of TgM83 transgenic mice, which express the A53T mutant form of human alpha-synuclein (αSyn), as well as into wild-type (WT) mice. We then assessed myelin protein expression and inflammatory responses. TgM83 mice injected with AAV-hSNCA exhibited demyelination, increased activation of microglia and astrocytes, and altered cytokine and chemokine profiles (including IL-1α, IL-10, IL-12(p40), CCL2, CCL3, CCL4, and CCL5), compared to both WT mice and TgM83 mice injected with AAV-eGFP. Interestingly, myelin basic protein (MBP) levels were significantly elevated around the injection site in TgM83 mice injected with AAV-hSNCA. Notably, we observed a positive correlation between MBP expression and inflammatory markers, as indicated by Iba1 and GFAP staining. These findings suggest that hSNCA overexpression is associated with increased MBP levels and enhanced inflammatory responses, implicating that MBP and myelination processes may play previously underappreciated roles in the pathogenesis of MSA. |
| format | Article |
| id | doaj-art-c0c17fb35122482884d4f7d587ff7fb1 |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-c0c17fb35122482884d4f7d587ff7fb12025-08-20T02:15:08ZengBMCActa Neuropathologica Communications2051-59602025-05-0113111810.1186/s40478-025-02014-yOligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophySam Chi-Hao Liu0Koping Chang1Meng-Ling Chen2Ming-Che Kuo3Teh-Cheng Wang4Ruey-Meei Wu5Department of Neurology, National Taiwan University College of MedicineDepartment of Pathology, National Taiwan University HospitalDepartment of Neurology, National Taiwan University College of MedicineDepartment of Neurology, National Taiwan University College of MedicineDepartment of Neurology, National Taiwan University College of MedicineDepartment of Neurology, National Taiwan University College of MedicineAbstract Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by parkinsonism, cerebellar dysfunction, and autonomic failure. Key pathological features of MSA include the formation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes (OLs), myelin loss, and neuroinflammation. Although both inflammation and myelination are known to be critical in MSA, the roles of myelin proteins and their relationship with inflammation have often been overlooked. In this study, we injected AAV-Olig001 vectors carrying either human SNCA (AAV-hSNCA) or eGFP (AAV-eGFP) into the striatum of TgM83 transgenic mice, which express the A53T mutant form of human alpha-synuclein (αSyn), as well as into wild-type (WT) mice. We then assessed myelin protein expression and inflammatory responses. TgM83 mice injected with AAV-hSNCA exhibited demyelination, increased activation of microglia and astrocytes, and altered cytokine and chemokine profiles (including IL-1α, IL-10, IL-12(p40), CCL2, CCL3, CCL4, and CCL5), compared to both WT mice and TgM83 mice injected with AAV-eGFP. Interestingly, myelin basic protein (MBP) levels were significantly elevated around the injection site in TgM83 mice injected with AAV-hSNCA. Notably, we observed a positive correlation between MBP expression and inflammatory markers, as indicated by Iba1 and GFAP staining. These findings suggest that hSNCA overexpression is associated with increased MBP levels and enhanced inflammatory responses, implicating that MBP and myelination processes may play previously underappreciated roles in the pathogenesis of MSA.https://doi.org/10.1186/s40478-025-02014-yMBPAAVOlig001TgM83 miceAlpha-synucleinopathyInflammation responsesMSA |
| spellingShingle | Sam Chi-Hao Liu Koping Chang Meng-Ling Chen Ming-Che Kuo Teh-Cheng Wang Ruey-Meei Wu Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy Acta Neuropathologica Communications MBP AAVOlig001 TgM83 mice Alpha-synucleinopathy Inflammation responses MSA |
| title | Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy |
| title_full | Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy |
| title_fullStr | Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy |
| title_full_unstemmed | Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy |
| title_short | Oligodendrocyte-specific overexpression of human alpha-synuclein results in elevated MBP levels and inflammatory responses in TgM83 mice, mimicking the pathological features of multiple system atrophy |
| title_sort | oligodendrocyte specific overexpression of human alpha synuclein results in elevated mbp levels and inflammatory responses in tgm83 mice mimicking the pathological features of multiple system atrophy |
| topic | MBP AAVOlig001 TgM83 mice Alpha-synucleinopathy Inflammation responses MSA |
| url | https://doi.org/10.1186/s40478-025-02014-y |
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