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

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.

Pubmed ID: 14713311


  • Moore DJ
  • Zhang L
  • Dawson TM
  • Dawson VL


Journal of neurochemistry

Publication Data

December 9, 2003

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS38377

Mesh Terms

  • Autoantigens
  • Blotting, Northern
  • Blotting, Western
  • Cell Line, Tumor
  • Cycloheximide
  • Electrophoresis, Gel, Pulsed-Field
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Leucine
  • Methionine
  • Mutation, Missense
  • Oncogene Proteins
  • Parkinsonian Disorders
  • Phenylalanine
  • Precipitin Tests
  • Protein Synthesis Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Ribonucleoproteins
  • Sulfur Isotopes
  • Transfection