Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration
Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson’s disease, but the mechanistic link between pUb elevat...
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eLife Sciences Publications Ltd
2025-07-01
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| Online Access: | https://elifesciences.org/articles/103945 |
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| author | Cong Chen Tong-Yao Gao Hua-Wei Yi Yi Zhang Tong Wang Zhi-Ling Lou Tao-Feng Wei Yun-Bi Lu Tingting Li Chun Tang Wei-Ping Zhang |
| author_facet | Cong Chen Tong-Yao Gao Hua-Wei Yi Yi Zhang Tong Wang Zhi-Ling Lou Tao-Feng Wei Yun-Bi Lu Tingting Li Chun Tang Wei-Ping Zhang |
| author_sort | Cong Chen |
| collection | DOAJ |
| description | Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson’s disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer’s disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration. |
| format | Article |
| id | doaj-art-5c1b9316fddd4b09ac400bbc9fe90fe4 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-5c1b9316fddd4b09ac400bbc9fe90fe42025-08-20T03:58:35ZengeLife Sciences Publications LtdeLife2050-084X2025-07-011410.7554/eLife.103945Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegenerationCong Chen0Tong-Yao Gao1Hua-Wei Yi2Yi Zhang3Tong Wang4Zhi-Ling Lou5Tao-Feng Wei6Yun-Bi Lu7Tingting Li8Chun Tang9https://orcid.org/0000-0001-6477-6500Wei-Ping Zhang10https://orcid.org/0000-0001-5229-5849Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou, ChinaThe First People’s Hospital of Jingzhou, First Affiliated Hospital of Yangtze University, Jingzhou, ChinaDepartment of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, ChinaBeijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Center for Quantitate Biology, Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, ChinaDepartment of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Key Laboratory of Precision Psychiatry, Hangzhou, ChinaUbiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson’s disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer’s disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.https://elifesciences.org/articles/103945PINK1phosphorylationproteasomeneurodegenerationubiquitin |
| spellingShingle | Cong Chen Tong-Yao Gao Hua-Wei Yi Yi Zhang Tong Wang Zhi-Ling Lou Tao-Feng Wei Yun-Bi Lu Tingting Li Chun Tang Wei-Ping Zhang Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration eLife PINK1 phosphorylation proteasome neurodegeneration ubiquitin |
| title | Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration |
| title_full | Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration |
| title_fullStr | Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration |
| title_full_unstemmed | Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration |
| title_short | Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration |
| title_sort | elevated ubiquitin phosphorylation by pink1 contributes to proteasomal impairment and promotes neurodegeneration |
| topic | PINK1 phosphorylation proteasome neurodegeneration ubiquitin |
| url | https://elifesciences.org/articles/103945 |
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