L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system.
Mutations in a gene on chromosome 1, DJ-1, have been reported recently to be associated with recessive, earlyonset Parkinson's disease. While one mutation is a large deletion that is predicted to produce an effective knockout of the gene, the second is a point mutation, L166P, whose precise effects on protein function are unclear. In the present study, we show that L166P destabilizes DJ-1 protein and promotes its degradation through the ubiquitin-proteasome system. A double mutant (K130R, L166P) was more stable than L166P, suggesting that this lysine residue contributes to stability of the protein. Subcellular localization was broadly similar for both wild type and L166P forms of the protein, indicating that the effect of the mutation is predominantly on protein stability. These observations are reminiscent of other recessive gene mutations that produce an effective loss of function. The L166P mutation has the simple effect of promoting DJ-1 degradation, thereby reducing net DJ-1 protein within the cell.
Miller
David W
DW
Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, Maryland 20892-1589, USA.
Ahmad
Rili
R
Hague
Stephen
S
Baptista
Melisa J
MJ
Canet-Aviles
Rosa
R
McLendon
Chris
C
Carter
Donald M
DM
Zhu
Peng-Peng
PP
Stadler
Julia
J
Chandran
Jayanth
J
Klinefelter
Gary R
GR
Blackstone
Craig
C
Cookson
Mark R
MR
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002845:Chromatography; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D005808:Genes, Recessive; D049452:Green Fluorescent Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics*; D017354:Point Mutation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D015513:Oncogene Proteins; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine