Parkinson's disease(PD)is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons.Emerging evidence suggests that deubiquitinating enzymes(DUBs),which regulate protein hom...Parkinson's disease(PD)is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons.Emerging evidence suggests that deubiquitinating enzymes(DUBs),which regulate protein homeostasis through the cleavage of ubiquitin chains,play critical roles in PD pathogenesis.In this study,we discovered that a DUB,ovarian tumor deubiquitinase 6A(OTUD6A),was significantly upregulated in both PD patients and PD mouse models.Notably,OTUD6A deficiency effectively protected dopaminergic neurons from degeneration and improved motor deficits in both acute and chronic PD mouse models.Through comprehensive mass spectrometry analysis and co-immunoprecipitation assays,we identified that actin gamma 1(ACTG1)serves as a key substrate of OTUD6A.Mechanistically,OTUD6A specifically interacts with the 8–181 aa domain of ACTG1 and preferentially cleaves K48-linked polyubiquitin chains,thereby enhancing ACTG1 protein stability in neuronal cells.The stabilized ACTG1 subsequently binds to p53 and facilitates its nuclear translocation,leading to the transcriptional activation of pro-apoptotic genes and promoting neuronal apoptosis.Collectively,our findings demonstrate that OTUD6A promotes dopaminergic neuron degeneration and PD progression by deubiquitinating and stabilizing ACTG1,which in turn activates a p53-dependent apoptotic pathway.These findings identify OTUD6A as a potential therapeutic target for PD intervention.展开更多
基金supported by the National Natural Science Foundation of China(21961142009 to Guang Liang and 82501725 to Xia Zhao)Hangzhou Natural Science Foundation(2024SZRYBH090002to Xia Zhao)Medical and Health Science and Technology Project of Zhejiang Province(2025KY1032 to Xia Zhao).
文摘Parkinson's disease(PD)is a severe neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons.Emerging evidence suggests that deubiquitinating enzymes(DUBs),which regulate protein homeostasis through the cleavage of ubiquitin chains,play critical roles in PD pathogenesis.In this study,we discovered that a DUB,ovarian tumor deubiquitinase 6A(OTUD6A),was significantly upregulated in both PD patients and PD mouse models.Notably,OTUD6A deficiency effectively protected dopaminergic neurons from degeneration and improved motor deficits in both acute and chronic PD mouse models.Through comprehensive mass spectrometry analysis and co-immunoprecipitation assays,we identified that actin gamma 1(ACTG1)serves as a key substrate of OTUD6A.Mechanistically,OTUD6A specifically interacts with the 8–181 aa domain of ACTG1 and preferentially cleaves K48-linked polyubiquitin chains,thereby enhancing ACTG1 protein stability in neuronal cells.The stabilized ACTG1 subsequently binds to p53 and facilitates its nuclear translocation,leading to the transcriptional activation of pro-apoptotic genes and promoting neuronal apoptosis.Collectively,our findings demonstrate that OTUD6A promotes dopaminergic neuron degeneration and PD progression by deubiquitinating and stabilizing ACTG1,which in turn activates a p53-dependent apoptotic pathway.These findings identify OTUD6A as a potential therapeutic target for PD intervention.
