摘要
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.
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.
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)
the Suzhou Clinical Research Center of Neurological Disease (Szzx201503)
a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions
