Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology
Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene, which encodes a ligand-dependent transcription factor. The mutant androgen receptor protein, characterized by polyglutamine expansion, is prone to misfolding...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2025-09-01
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| Series: | Neural Regeneration Research |
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| Online Access: | https://journals.lww.com/10.4103/NRR.NRR-D-23-01666 |
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| author | Yiyang Qin Wenzhen Zhu Tingting Guo Yiran Zhang Tingting Xing Peng Yin Shihua Li Xiao-Jiang Li Su Yang |
| author_facet | Yiyang Qin Wenzhen Zhu Tingting Guo Yiran Zhang Tingting Xing Peng Yin Shihua Li Xiao-Jiang Li Su Yang |
| author_sort | Yiyang Qin |
| collection | DOAJ |
| description | Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene, which encodes a ligand-dependent transcription factor. The mutant androgen receptor protein, characterized by polyglutamine expansion, is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients. These aggregates alter protein–protein interactions and compromise transcriptional activity. In this study, we reported that in both cultured N2a cells and mouse brain, mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-derived neurotrophic factor. Overexpression of mesencephalic astrocyte-derived neurotrophic factor ameliorated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation. Conversely, knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation. Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy. |
| format | Article |
| id | doaj-art-b17b54e03c164c3cb2ceeca9862274de |
| institution | OA Journals |
| issn | 1673-5374 1876-7958 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj-art-b17b54e03c164c3cb2ceeca9862274de2025-08-20T02:18:01ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53741876-79582025-09-012092655266610.4103/NRR.NRR-D-23-01666Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathologyYiyang QinWenzhen ZhuTingting GuoYiran ZhangTingting XingPeng YinShihua LiXiao-Jiang LiSu YangSpinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene, which encodes a ligand-dependent transcription factor. The mutant androgen receptor protein, characterized by polyglutamine expansion, is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients. These aggregates alter protein–protein interactions and compromise transcriptional activity. In this study, we reported that in both cultured N2a cells and mouse brain, mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-derived neurotrophic factor. Overexpression of mesencephalic astrocyte-derived neurotrophic factor ameliorated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation. Conversely, knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation. Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.https://journals.lww.com/10.4103/NRR.NRR-D-23-01666androgen receptormesencephalic astrocyte-derived neurotrophic factormouse modelneurodegenerationneuronal lossneurotrophic factorpolyglutamine diseaseprotein misfoldingspinal and bulbar muscular atrophytranscription factor |
| spellingShingle | Yiyang Qin Wenzhen Zhu Tingting Guo Yiran Zhang Tingting Xing Peng Yin Shihua Li Xiao-Jiang Li Su Yang Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology Neural Regeneration Research androgen receptor mesencephalic astrocyte-derived neurotrophic factor mouse model neurodegeneration neuronal loss neurotrophic factor polyglutamine disease protein misfolding spinal and bulbar muscular atrophy transcription factor |
| title | Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology |
| title_full | Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology |
| title_fullStr | Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology |
| title_full_unstemmed | Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology |
| title_short | Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology |
| title_sort | reduced mesencephalic astrocyte derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology |
| topic | androgen receptor mesencephalic astrocyte-derived neurotrophic factor mouse model neurodegeneration neuronal loss neurotrophic factor polyglutamine disease protein misfolding spinal and bulbar muscular atrophy transcription factor |
| url | https://journals.lww.com/10.4103/NRR.NRR-D-23-01666 |
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