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

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.
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
Hum. Mol. Genet.
Date: Jun. 01, 2006
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