title: Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease.
abstract: Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD). We here report identification of a family with PD patients harboring novel heterozygous missense mutations in both PINK1 and DJ-1 genes encoding DJ-1A39S and PINK1P399L, respectively. In transfected cells, DJ-1 interacts with PINK1. PINK1P399L is less stable than the wild-type protein and is degraded via the ubiquitin-mediated proteasomal pathway. Expression of wild-type DJ-1 increased steady-state levels of PINK1, whereas expression of DJ-1A39S reduced steady-state levels of PINK1. Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP(+))-induced death of dopaminergic SH-SY5Y cells. In contrast, co-expression of PD-associated DJ-1A39S and PINK1P399L significantly potentiated susceptibility of SH-SY5Y cells to MPP(+)-induced cell death. This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.
authors.affiliation: National Laboratory of Medical Genetics, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
authors.forename: Beisha
authors.initials: B
authors.lastname: Tang
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.forename: Yuhu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Hu
authors.forename: Zanhua
authors.initials: Z
authors.lastname: Zhu
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Qian
authors.initials: Q
authors.lastname: Pan
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Xia
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D000099202:PTEN-Induced Putative Kinase
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C105131:PARK7 protein, human