Parkinson＇s disease（PD） is the most common neurodegenerative movement disorder. Mutations in the DJ-1, including L166 P, are responsible for recessive earlyonset PD. Many lines of evidence have shown that L166 P is...Parkinson＇s disease（PD） is the most common neurodegenerative movement disorder. Mutations in the DJ-1, including L166 P, are responsible for recessive earlyonset PD. Many lines of evidence have shown that L166 P is not only a loss-of-function mutant, but also a proapoptotic-like protein that results in mitochondrial dysfunction. L166 P has been reported to be unstable and to mislocalize to mitochondria. However, the mechanisms underlying the instability of L166 P compared to wild-type DJ-1 remain largely unknown. Here, we showed that Omi/Htr A2, a mitochondrial serine protease that has also been linked to the pathogenesis of PD, contributed to L166 P instability. Omi directly interacted with and cleaved L166 P in mitochondria to decrease the L166 P level. However,Omi did not bind and cleave wild-type DJ-1. Moreover,Omi cleaved L166 P at both serine residues 3 and 121,while L166 P-induced cell death under H_2O_2 treatment was alleviated by over-expression of Omi. Our data reveal a bridge between DJ-1 and Omi, two PD-associated geneticfactors, which contributes to our understanding of the pathogenesis of PD.展开更多
基金supported by the National Key Scientific R&D Program of China (2016YFC1306000)the National Natural Sciences Foundation of China (31471012, 81761148024, 31330030, and 81371393)+1 种基金the Suzhou Clinical Research Center of Neurological Disease (Szzx201503)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Parkinson＇s disease（PD） is the most common neurodegenerative movement disorder. Mutations in the DJ-1, including L166 P, are responsible for recessive earlyonset PD. Many lines of evidence have shown that L166 P is not only a loss-of-function mutant, but also a proapoptotic-like protein that results in mitochondrial dysfunction. L166 P has been reported to be unstable and to mislocalize to mitochondria. However, the mechanisms underlying the instability of L166 P compared to wild-type DJ-1 remain largely unknown. Here, we showed that Omi/Htr A2, a mitochondrial serine protease that has also been linked to the pathogenesis of PD, contributed to L166 P instability. Omi directly interacted with and cleaved L166 P in mitochondria to decrease the L166 P level. However,Omi did not bind and cleave wild-type DJ-1. Moreover,Omi cleaved L166 P at both serine residues 3 and 121,while L166 P-induced cell death under H_2O_2 treatment was alleviated by over-expression of Omi. Our data reveal a bridge between DJ-1 and Omi, two PD-associated geneticfactors, which contributes to our understanding of the pathogenesis of PD.
