title: Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6.
abstract: Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson's disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimicking the clinical picture of PD with earlier onset and slower progression. Genetic data demonstrated PARK6 to be caused by mutations in the protein PINK1, which is localized to mitochondria and has a serine-threonine kinase domain. To study the effect of PINK1 mutations on oxidative stress, we used primary fibroblasts and immortalized lymphoblasts from three patients homozygous for G309D-PINK1. Oxidative stress was evident from increases in lipid peroxidation and in antioxidant defenses by mitochondrial superoxide dismutase and glutathione. Elevated levels of glutathione reductase and glutathione-S-transferase were also observed. As a putative cause of oxidation, a mild decrease in complex I activity and a trend to superoxide elevation were detectable. These data indicate that PINK1 function is critical to prevent oxidative damage and that peripheral cells may be useful for studies of progression and therapy of PARK6.
authors.affiliation: Section for Molecular Neurogenetics, Clinic for Neurology, University Hospital, Theodor Stern Kai 7, 60590 Frankfurt/M., Germany.
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Hoepken
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.forename: Blas
authors.initials: B
authors.lastname: Morales
authors.forename: Oliver
authors.initials: O
authors.lastname: Wingerter
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Turco
authors.forename: Alexander
authors.initials: A
authors.lastname: Mülsch
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Alexei P
authors.initials: AP
authors.lastname: Kudin
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
mesh_terms: D000328:Adult; D002461:Cell Line, Transformed; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D042967:Electron Transport Complex I; D005978:Glutathione; D011494:Protein Kinases; D013482:Superoxide Dismutase; D013481:Superoxides; D000099202:PTEN-Induced Putative Kinase