A missense mutation (L166P) in DJ‐1, linked to familial Parkinson's disease, confers reduced protein stability and impairs homo‐oligomerization

• DOI: 10.1111/j.1471-4159.2003.02265.x
• Publication Date: 2010-07-29T01:39:45Z
• Authors: Darren J. Moore; Li Zhang; Ted M. Dawson; Valina L. Dawson
• Keywords: Loss function; Mutant protein

The identification of genetic mutations responsible for rare familial forms Parkinson's disease (PD) have provided tremendous insight into the molecular pathogenesis this disorder. Mutations in DJ-1 gene cause autosomal recessive early onset PD two European families. A Dutch kindred displays a large homozygous genomic deletion encompassing exons 1-5 gene, whereas an Italian harbors single L166P missense mutation. M26I mutation was also recently reported Ashkenazi Jewish patient with PD. are predicted to be loss function. recent determination crystal structure human demonstrates that it exists homo-dimeric form vitro, mutant only as monomer. Here, we examine vivo effects pathogenic and on properties cell culture. We report confers markedly reduced protein stability DJ-1, which results from enhanced degradation by 20S/26S proteasome but not mRNA expression. Furthermore, exhibits impaired ability self-interact homo-oligomers. In contrast, does appear adversely affect either stability, turnover proteasome, or capacity These may contribute normal function likely underlying affected members kindred.