title: DJ-1 promotes the proteasomal degradation of Fis1: implications of DJ-1 in neuronal protection.
abstract: Mutations in DJ-1/PARK7 (Parkinson protein 7) have been identified as a cause of autosomal-recessive PD (Parkinson's disease) and the antioxidant property of DJ-1 has been shown to be involved in the regulation of mitochondrial function and neuronal cell survival. In the present study, we first found that the DJ-1 transgene mitigated MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced DA (dopamine) neuron cell death and cell loss. We then observed that the protein levels of DJ-1 were significantly decreased, whereas levels of Fis1 [fission 1 (mitochondrial outer membrane) homologue] were noticeably increased in the striatum of MPTP-treated mice. In addition to our identification of RNF5 (RING-finger protein-5) as an E3-ligase for Fis1 ubiquitination, we demonstrated the involvement of the DJ-1/Akt/RNF5 signalling pathway in the regulation of Fis1 proteasomal degradation. In other experiments, we found that Akt1 enhances the mitochondrial translocation and E3-ligase activity of RNF5, leading to Fis1 degradation. Together, the identification of Fis1 degradation by DJ-1 signalling in the regulation of oxidative stress-induced neuronal cell death supplies a novel mechanism of DJ-1 in neuronal protection with the implication of DJ-1 in a potential therapeutic avenue for PD.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Junbing
authors.initials: J
authors.lastname: Wu
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Guiping
authors.initials: G
authors.lastname: Du
authors.forename: Renjie
authors.initials: R
authors.lastname: Jiao
authors.forename: Yong
authors.initials: Y
authors.lastname: Tian
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zheng
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000503:physiopathology; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
chemical_list: C561064:FIS1 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D015513:Oncogene Proteins; D054464:Peroxiredoxins; C529960:RNF5 protein, mouse; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D046988:Proteasome Endopeptidase Complex