Mutant HTT does not affect glial development but impairs myelination in the early disease stage
IntroductionHuntington’s disease (HD) is caused by expanded CAG repeats in the huntingtin gene (HTT) and is characterized by late-onset neurodegeneration that primarily affects the striatum. Several studies have shown that mutant HTT can also affect neuronal development, contributing to the late-ons...
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| Format: | Article |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2023.1238306/full |
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| author | Sitong Yang Jingjing Ma Han Zhang Laiqiang Chen Yuxuan Li Mingtian Pan Hongcheng Zhu Jun Liang Dajian He Shihua Li Xiao-Jiang Li Xiangyu Guo |
| author_facet | Sitong Yang Jingjing Ma Han Zhang Laiqiang Chen Yuxuan Li Mingtian Pan Hongcheng Zhu Jun Liang Dajian He Shihua Li Xiao-Jiang Li Xiangyu Guo |
| author_sort | Sitong Yang |
| collection | DOAJ |
| description | IntroductionHuntington’s disease (HD) is caused by expanded CAG repeats in the huntingtin gene (HTT) and is characterized by late-onset neurodegeneration that primarily affects the striatum. Several studies have shown that mutant HTT can also affect neuronal development, contributing to the late-onset neurodegeneration. However, it is currently unclear whether mutant HTT impairs the development of glial cells, which is important for understanding whether mutant HTT affects glial cells during early brain development.MethodsUsing HD knock-in mice that express full-length mutant HTT with a 140 glutamine repeat at the endogenous level, we analyzed the numbers of astrocytes and oligodendrocytes from postnatal day 1 to 3 months of age via Western blotting and immunocytochemistry. We also performed electron microscopy, RNAseq analysis, and quantitative RT-PCR.ResultsThe numbers of astrocytes and oligodendrocytes were not significantly altered in postnatal HD KI mice compared to wild type (WT) mice. Consistently, glial protein expression levels were not significantly different between HD KI and WT mice. However, at 3 months of age, myelin protein expression was reduced in HD KI mice, as evidenced by Western blotting and immunocytochemical results. Electron microscopy revealed a slight but significant reduction in myelin thickness of axons in the HD KI mouse brain at 3 months of age. RNAseq analysis did not show significant reductions in myelin-related genes in postnatal HD KI mice.ConclusionThese data suggest that cytoplasmic mutant HTT, rather than nuclear mutant HTT, mediates myelination defects in the early stages of the disease without impacting the differentiation and maturation of glial cells. |
| first_indexed | 2024-03-12T23:03:58Z |
| format | Article |
| id | doaj.art-aff27d5ebc0a4ded9d942d25cb2f405e |
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| issn | 1662-453X |
| language | English |
| last_indexed | 2024-03-12T23:03:58Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-aff27d5ebc0a4ded9d942d25cb2f405e2023-07-19T05:26:54ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2023-07-011710.3389/fnins.2023.12383061238306Mutant HTT does not affect glial development but impairs myelination in the early disease stageSitong YangJingjing MaHan ZhangLaiqiang ChenYuxuan LiMingtian PanHongcheng ZhuJun LiangDajian HeShihua LiXiao-Jiang LiXiangyu GuoIntroductionHuntington’s disease (HD) is caused by expanded CAG repeats in the huntingtin gene (HTT) and is characterized by late-onset neurodegeneration that primarily affects the striatum. Several studies have shown that mutant HTT can also affect neuronal development, contributing to the late-onset neurodegeneration. However, it is currently unclear whether mutant HTT impairs the development of glial cells, which is important for understanding whether mutant HTT affects glial cells during early brain development.MethodsUsing HD knock-in mice that express full-length mutant HTT with a 140 glutamine repeat at the endogenous level, we analyzed the numbers of astrocytes and oligodendrocytes from postnatal day 1 to 3 months of age via Western blotting and immunocytochemistry. We also performed electron microscopy, RNAseq analysis, and quantitative RT-PCR.ResultsThe numbers of astrocytes and oligodendrocytes were not significantly altered in postnatal HD KI mice compared to wild type (WT) mice. Consistently, glial protein expression levels were not significantly different between HD KI and WT mice. However, at 3 months of age, myelin protein expression was reduced in HD KI mice, as evidenced by Western blotting and immunocytochemical results. Electron microscopy revealed a slight but significant reduction in myelin thickness of axons in the HD KI mouse brain at 3 months of age. RNAseq analysis did not show significant reductions in myelin-related genes in postnatal HD KI mice.ConclusionThese data suggest that cytoplasmic mutant HTT, rather than nuclear mutant HTT, mediates myelination defects in the early stages of the disease without impacting the differentiation and maturation of glial cells.https://www.frontiersin.org/articles/10.3389/fnins.2023.1238306/fullHuntington’s diseasegliadevelopmentdemyelinationoligodendrocyte |
| spellingShingle | Sitong Yang Jingjing Ma Han Zhang Laiqiang Chen Yuxuan Li Mingtian Pan Hongcheng Zhu Jun Liang Dajian He Shihua Li Xiao-Jiang Li Xiangyu Guo Mutant HTT does not affect glial development but impairs myelination in the early disease stage Frontiers in Neuroscience Huntington’s disease glia development demyelination oligodendrocyte |
| title | Mutant HTT does not affect glial development but impairs myelination in the early disease stage |
| title_full | Mutant HTT does not affect glial development but impairs myelination in the early disease stage |
| title_fullStr | Mutant HTT does not affect glial development but impairs myelination in the early disease stage |
| title_full_unstemmed | Mutant HTT does not affect glial development but impairs myelination in the early disease stage |
| title_short | Mutant HTT does not affect glial development but impairs myelination in the early disease stage |
| title_sort | mutant htt does not affect glial development but impairs myelination in the early disease stage |
| topic | Huntington’s disease glia development demyelination oligodendrocyte |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2023.1238306/full |
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