Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease
Abstract Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, i...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409477 |
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| author | Shuke Nie Bowei Li Mengmeng Wang Zijun Chen Jiayan Ren Zixuan Li Xinli Xu Zhengjiang Qian Zhongyun Xie Jianxin Han Zhentao Zhang Zhaohui Zhang Yingjie Zhu Zuxin Chen Xifei Yang Keqiang Ye |
| author_facet | Shuke Nie Bowei Li Mengmeng Wang Zijun Chen Jiayan Ren Zixuan Li Xinli Xu Zhengjiang Qian Zhongyun Xie Jianxin Han Zhentao Zhang Zhaohui Zhang Yingjie Zhu Zuxin Chen Xifei Yang Keqiang Ye |
| author_sort | Shuke Nie |
| collection | DOAJ |
| description | Abstract Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY‐box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6+/ALDH1A1+) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT‐rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT‐rich DNA sequences, and toxic dopamine metabolite accumulation. AEP cuts Sox6 and ALDH1A1 in dopaminergic neurons that project to the locus coeruleus (LC), abolishing Sox6's transcriptive and ALDH1A1's enzymatic activities. Co‐expressing AEP‐truncated Sox6 and ALDH1A1 fragments in 3‐month‐old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP‐resistant Sox6 N336A/N446A and ALDH1A1 N220A mutants alleviates rotenone‐induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD. |
| format | Article |
| id | doaj-art-46afc9a6db474c7fbdde8426dcbe73dd |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-46afc9a6db474c7fbdde8426dcbe73dd2025-01-13T15:29:43ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202409477Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's DiseaseShuke Nie0Bowei Li1Mengmeng Wang2Zijun Chen3Jiayan Ren4Zixuan Li5Xinli Xu6Zhengjiang Qian7Zhongyun Xie8Jianxin Han9Zhentao ZhangZhaohui Zhang10Yingjie Zhu11Zuxin Chen12Xifei Yang13Keqiang Ye14Department of Neurology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaBrain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT) Chinese Academy of Sciences Shenzhen Guangdong 518055 ChinaBrain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT) Chinese Academy of Sciences Shenzhen Guangdong 518055 ChinaShenzhen Key Laboratory of Drug Addiction Shenzhen Neher Neural Plasticity Laboratory BCBDI SIAT Chinese Academy of Sciences Shenzhen‐Hong Kong Institute of Brain Science‐Shenzhen Fundamental Research Institutions Shenzhen 518055 ChinaGuangdong Provincial Key Laboratory of Brain Connectome and Behavior CAS Key Laboratory of Brain Connectome and Manipulation BCBDI SIAT Chinese Academy of Sciences Shenzhen 518055 ChinaGuangdong Provincial Key Laboratory of Brain Connectome and Behavior CAS Key Laboratory of Brain Connectome and Manipulation BCBDI SIAT Chinese Academy of Sciences Shenzhen 518055 ChinaGuangdong Provincial Key Laboratory of Brain Connectome and Behavior CAS Key Laboratory of Brain Connectome and Manipulation BCBDI SIAT Chinese Academy of Sciences Shenzhen 518055 ChinaBrain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT) Chinese Academy of Sciences Shenzhen Guangdong 518055 ChinaBrain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT) Chinese Academy of Sciences Shenzhen Guangdong 518055 ChinaBrain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT) Chinese Academy of Sciences Shenzhen Guangdong 518055 ChinaDepartment of Neurology Renmin Hospital of Wuhan University Wuhan Hubei 430060 ChinaShenzhen Key Laboratory of Drug Addiction Shenzhen Neher Neural Plasticity Laboratory BCBDI SIAT Chinese Academy of Sciences Shenzhen‐Hong Kong Institute of Brain Science‐Shenzhen Fundamental Research Institutions Shenzhen 518055 ChinaGuangdong Provincial Key Laboratory of Brain Connectome and Behavior CAS Key Laboratory of Brain Connectome and Manipulation BCBDI SIAT Chinese Academy of Sciences Shenzhen 518055 ChinaKey Laboratory of Modern Toxicology of Shenzhen Shenzhen Medical Key Discipline of Health Toxicology (2020‐2024) Shenzhen Center for Disease Control and Prevention Shenzhen Guangdong 518055 ChinaBrain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology (SIAT) Chinese Academy of Sciences Shenzhen Guangdong 518055 ChinaAbstract Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY‐box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6+/ALDH1A1+) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT‐rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT‐rich DNA sequences, and toxic dopamine metabolite accumulation. AEP cuts Sox6 and ALDH1A1 in dopaminergic neurons that project to the locus coeruleus (LC), abolishing Sox6's transcriptive and ALDH1A1's enzymatic activities. Co‐expressing AEP‐truncated Sox6 and ALDH1A1 fragments in 3‐month‐old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP‐resistant Sox6 N336A/N446A and ALDH1A1 N220A mutants alleviates rotenone‐induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD.https://doi.org/10.1002/advs.202409477ALDH1A1asparagine endopeptidaseparkinson's diseaseSox6vulnerability |
| spellingShingle | Shuke Nie Bowei Li Mengmeng Wang Zijun Chen Jiayan Ren Zixuan Li Xinli Xu Zhengjiang Qian Zhongyun Xie Jianxin Han Zhentao Zhang Zhaohui Zhang Yingjie Zhu Zuxin Chen Xifei Yang Keqiang Ye Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease Advanced Science ALDH1A1 asparagine endopeptidase parkinson's disease Sox6 vulnerability |
| title | Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease |
| title_full | Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease |
| title_fullStr | Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease |
| title_full_unstemmed | Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease |
| title_short | Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease |
| title_sort | sox6 and aldh1a1 truncation by asparagine endopeptidase defines selective neuronal vulnerability in parkinson s disease |
| topic | ALDH1A1 asparagine endopeptidase parkinson's disease Sox6 vulnerability |
| url | https://doi.org/10.1002/advs.202409477 |
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