PMID:14713311

Citation	Moore, DJ, Zhang, L, Dawson, TM and Dawson, VL (2003) A missense mutation (L166P) in DJ-1, linked to familial Parkinson's disease, confers reduced protein stability and impairs homo-oligomerization. J. Neurochem. 87:1558-67
Abstract	The identification of genetic mutations responsible for rare familial forms of Parkinson's disease (PD) have provided tremendous insight into the molecular pathogenesis of this disorder. Mutations in the DJ-1 gene cause autosomal recessive early onset PD in two European families. A Dutch kindred displays a large homozygous genomic deletion encompassing exons 1-5 of the DJ-1 gene, whereas an Italian kindred harbors a single homozygous L166P missense mutation. A homozygous M26I missense mutation was also recently reported in an Ashkenazi Jewish patient with early onset PD. Mutations in DJ-1 are predicted to be loss of function. The recent determination of the crystal structure of human DJ-1 demonstrates that it exists in a homo-dimeric form in vitro, whereas the L166P mutant exists only as a monomer. Here, we examine the in vivo effects of the pathogenic L166P and M26I mutations on the properties of DJ-1 in cell culture. We report that the L166P mutation confers markedly reduced protein stability to DJ-1, which results from enhanced degradation by the 20S/26S proteasome but not from a loss of mRNA expression. Furthermore, the L166P mutant protein exhibits an impaired ability to self-interact to form homo-oligomers. In contrast, the M26I mutation does not appear to adversely affect either protein stability, turnover by the proteasome, or the capacity of DJ-1 to form homo-oligomers. These properties of the L166P mutation may contribute to the loss of normal DJ-1 function and are likely to be the underlying cause of early onset PD in affected members of the Italian kindred.
Links	PubMed
Keywords	Autoantigens; Blotting, Northern; Blotting, Western/methods; Cell Line, Tumor; Cycloheximide/pharmacology; Electrophoresis, Gel, Pulsed-Field/methods; Humans; Intracellular Signaling Peptides and Proteins; Leucine/genetics; Methionine/pharmacokinetics; Mutation, Missense; Oncogene Proteins/genetics; Oncogene Proteins/immunology; Parkinsonian Disorders/genetics; Parkinsonian Disorders/metabolism; Phenylalanine/genetics; Precipitin Tests/methods; Protein Synthesis Inhibitors/pharmacology; Proteins/metabolism; Proto-Oncogene Proteins c-myc/metabolism; RNA, Messenger/metabolism; Ribonucleoproteins/metabolism; Sulfur Isotopes/pharmacokinetics; Transfection/methods
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