Proteomic identification of a stress protein, mortalin/mthsp70/GRP75: relevance to Parkinson disease.
Functional impairment of mitochondria and proteasomes and increased oxidative damage comprise the main pathological phenotypes of Parkinson disease (PD). Using an unbiased quantitative proteomic approach, we compared nigral mitochondrial proteins of PD patients with those from age-matched controls. 119 of 842 identified proteins displayed significant differences in their relative abundance (increase/decrease) between the two groups. We confirmed that one of these, mortalin (mthsp70/GRP75, a mitochondrial stress protein), is substantially decreased in PD brains as well as in a cellular model of PD. In addition, nine candidate mortalin-binding partners were identified as potential mediators of PD pathology. Manipulations of mortalin level in dopaminergic neurons resulted in significant changes in sensitivity to PD phenotypes via pathways involving mitochondrial and proteasomal function as well as oxidative stress.
Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98104, USA.
Jinghua
J
Jin
Christine
C
Hulette
Yan
Y
Wang
Terry
T
Zhang
Catherine
C
Pan
Renu
R
Wadhwa
Jing
J
Zhang
D000367:Age Factors; D015153:Blotting, Western; D016022:Case-Control Studies; D002458:Cell Fractionation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D018840:HSP70 Heat-Shock Proteins / Q000302:isolation & purification* / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000032:analysis*; D006801:Humans; D024101:Mitochondrial Proteins / Q000302:isolation & purification / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D040901:Proteomics; D015203:Reproducibility of Results; D012402:Rotenone / Q000633:toxicity; D020539:Sequence Analysis, Protein; D014162:Transfection
D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; C080352:mortalin; D012402:Rotenone; D046988:Proteasome Endopeptidase Complex