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.
Moore
Darren J
DJ
Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Zhang
Li
L
Dawson
Ted M
TM
Dawson
Valina L
VL
D001324:Autoantigens; D015152:Blotting, Northern; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D016521:Electrophoresis, Gel, Pulsed-Field / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000235:genetics; D008715:Methionine / Q000493:pharmacokinetics; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000235:genetics* / Q000276:immunology; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D010649:Phenylalanine / Q000235:genetics; D011233:Precipitin Tests / Q000379:methods; D000071617:Protein Deglycase DJ-1; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D014162:Transfection / Q000379:methods; D000097585:SS-B Antigen
D001324:Autoantigens; D003513:Cycloheximide; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D008715:Methionine; D015513:Oncogene Proteins; D010649:Phenylalanine; D000071617:Protein Deglycase DJ-1; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D013460:Sulfur Isotopes; D000097585:SS-B Antigen; C105131:PARK7 protein, human