title: The E163K DJ-1 mutant shows specific antioxidant deficiency.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, 125 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
authors.forename: Chenere P
authors.initials: CP
authors.lastname: Ramsey
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology*; D054464:Peroxiredoxins; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D000071617:Protein Deglycase DJ-1; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology; D055550:Protein Stability; D012995:Solubility; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D054464:Peroxiredoxins; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D046988:Proteasome Endopeptidase Complex