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Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease.

Human molecular genetics | Jun 1, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16632486

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.

Pubmed ID: 16632486 RIS Download

Mesh terms: Adult | Age of Onset | Amino Acid Sequence | Cell Line, Tumor | Female | Genetic Predisposition to Disease | Humans | Intracellular Signaling Peptides and Proteins | Male | Middle Aged | Molecular Sequence Data | Mutation, Missense | Oncogene Proteins | Parkinson Disease | Pedigree | Protein Kinases | Sequence Homology, Amino Acid

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