Ubiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway
Abstract Background Mitochondrial dysfunction and neuronal damage are major sign of cytopathology in Huntington’s disease (HD), a neurodegenerative disease. Ubiquitin specific peptidase 11 (USP11) is a deubiquitinating enzyme involved in various physiological processes through regulating protein deg...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s10020-024-01061-w |
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| author | Bai Gao Yuchen Jing Xi Li Shuyan Cong |
| author_facet | Bai Gao Yuchen Jing Xi Li Shuyan Cong |
| author_sort | Bai Gao |
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| description | Abstract Background Mitochondrial dysfunction and neuronal damage are major sign of cytopathology in Huntington’s disease (HD), a neurodegenerative disease. Ubiquitin specific peptidase 11 (USP11) is a deubiquitinating enzyme involved in various physiological processes through regulating protein degradation. However, its specific role in HD is unclear. Methods To interfere with USP11 expression, adeno-associated viruses 2 containing USP11-specific shRNA were injected into the bilateral striatum of 12-week-old R6/1 and WT mice. In vitro, the inducible PC12 cell model of HD was used in which the expression of an N-terminal truncation of huntingtin, with either wild type (Q23) or expanded polyglutamine (Q74) can be induced by the doxycycline. USP11 was knocked down to study its role in HD. The protein expression patterns in Q74 cells were quantified by label-free proteomics to further explore the target protein of USP11. Detecting the association between USP11 and Phosphatase and Tensin Homolog (PTEN) through Co-IP. Results Herein, USP11 was found to be upregulated in the striatum of R6/1 mice (an HD model with gradual development of symptoms) in an age-dependent manner. The spontaneous HD was alleviated by silencing USP11, as evidenced by improved locomotor activity and spatial memory, attenuated striatal atrophy in R6/1 mice, reduced accumulation of mutant huntingtin protein, and restored mitochondrial function in vitro and in vivo. The results of label-free proteomics revealed a significant change in the protein expression profile. Through functional enrichment, we focused on PTEN, known as a negative regulator of the AKT pathway. We demonstrated that USP11 downregulation promoted ubiquitination modification of PTEN and activated the AKT pathway, and PTEN overexpression reversed the effects of USP11 knockdown. Conclusions Collectively, USP11 knockdown protects R6/1 mouse neurons from oxidative stress by alleviating mitochondrial dysfunction, thereby preventing the HD progression. This is achieved by inhibiting PTEN expression, which in turn activates the AKT pathway. This study suggests that USP11-PTEN-AKT signaling pathway may be a new attractive therapeutic target for HD. |
| format | Article |
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| language | English |
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| series | Molecular Medicine |
| spelling | doaj-art-452bd797bf914d9daec0fa404d5bc9162025-08-20T02:28:08ZengBMCMolecular Medicine1528-36582025-01-0131112010.1186/s10020-024-01061-wUbiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathwayBai Gao0Yuchen Jing1Xi Li2Shuyan Cong3Department of Neurology, Shengjing Hospital of China Medical UniversityDepartment of Vascular Surgery, The First Hospital of China Medical UniversityDepartment of Vascular Surgery, The First Hospital of China Medical UniversityDepartment of Neurology, Shengjing Hospital of China Medical UniversityAbstract Background Mitochondrial dysfunction and neuronal damage are major sign of cytopathology in Huntington’s disease (HD), a neurodegenerative disease. Ubiquitin specific peptidase 11 (USP11) is a deubiquitinating enzyme involved in various physiological processes through regulating protein degradation. However, its specific role in HD is unclear. Methods To interfere with USP11 expression, adeno-associated viruses 2 containing USP11-specific shRNA were injected into the bilateral striatum of 12-week-old R6/1 and WT mice. In vitro, the inducible PC12 cell model of HD was used in which the expression of an N-terminal truncation of huntingtin, with either wild type (Q23) or expanded polyglutamine (Q74) can be induced by the doxycycline. USP11 was knocked down to study its role in HD. The protein expression patterns in Q74 cells were quantified by label-free proteomics to further explore the target protein of USP11. Detecting the association between USP11 and Phosphatase and Tensin Homolog (PTEN) through Co-IP. Results Herein, USP11 was found to be upregulated in the striatum of R6/1 mice (an HD model with gradual development of symptoms) in an age-dependent manner. The spontaneous HD was alleviated by silencing USP11, as evidenced by improved locomotor activity and spatial memory, attenuated striatal atrophy in R6/1 mice, reduced accumulation of mutant huntingtin protein, and restored mitochondrial function in vitro and in vivo. The results of label-free proteomics revealed a significant change in the protein expression profile. Through functional enrichment, we focused on PTEN, known as a negative regulator of the AKT pathway. We demonstrated that USP11 downregulation promoted ubiquitination modification of PTEN and activated the AKT pathway, and PTEN overexpression reversed the effects of USP11 knockdown. Conclusions Collectively, USP11 knockdown protects R6/1 mouse neurons from oxidative stress by alleviating mitochondrial dysfunction, thereby preventing the HD progression. This is achieved by inhibiting PTEN expression, which in turn activates the AKT pathway. This study suggests that USP11-PTEN-AKT signaling pathway may be a new attractive therapeutic target for HD.https://doi.org/10.1186/s10020-024-01061-wHuntington’s disease (HD)Ubiquitin specific peptidase 11 (USP11)Phosphatase and tensin homolog (PTEN)Neuronal apoptosisMitochondria |
| spellingShingle | Bai Gao Yuchen Jing Xi Li Shuyan Cong Ubiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway Molecular Medicine Huntington’s disease (HD) Ubiquitin specific peptidase 11 (USP11) Phosphatase and tensin homolog (PTEN) Neuronal apoptosis Mitochondria |
| title | Ubiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway |
| title_full | Ubiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway |
| title_fullStr | Ubiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway |
| title_full_unstemmed | Ubiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway |
| title_short | Ubiquitin specific peptidase 11 knockdown slows Huntington’s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway |
| title_sort | ubiquitin specific peptidase 11 knockdown slows huntington s disease progression via regulating mitochondrial dysfunction and neuronal damage depending on pten mediated akt pathway |
| topic | Huntington’s disease (HD) Ubiquitin specific peptidase 11 (USP11) Phosphatase and tensin homolog (PTEN) Neuronal apoptosis Mitochondria |
| url | https://doi.org/10.1186/s10020-024-01061-w |
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