期刊
BRAIN RESEARCH
卷 1239, 期 -, 页码 1-11出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2008.09.009
关键词
Parkinson's disease; DJ-1; Oxidative stress; Mitochondria
资金
- National Institute on Aging [AG09215]
- National Institute on General Medicine Sciences [GM082026]
Recent discoveries of genetic mutations linked to familial forms of Parkinson's disease (PD), including mutations in DJ-1, have provided insights into the pathogenesis of sporadic PD. Recently, a novel homozygous missense mutation in the gene encoding human DJ-1 protein resulting in the E163K amino acid substitution has been reported. This mutation is associated with early-onset and clinical presentations that include parkinsonism, cognitive decline, and amyotrophic lateral sclerosis. The specific effect of this mutation on the function of DJ-1 protein as it relates to disease pathogenesis is currently unknown. Herein we show that the E163K pathogenic mutant retains similar properties to wild-type DJ-1 protein as it relates to protein stability, solubility, and dimerization. However, we show that the E163K mutant loses the ability to protect against oxidative stress while demonstrating a reduced redistribution towards mitochondria, but retains the ability to mitigate toxicity due to mitochondrial stress and proteasomal impairment. These findings suggest that DJ-1 influences several neuroprotective pathways and that the E163K mutation impairs the mechanism that is more specific to oxidative stress. (C) 2008 Elsevier B.V. All rights reserved.
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