Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6

• Published in: Neurobiology of disease Vol. 25; no. 2; pp. 401 - 411
• Main Authors: Hoepken, Hans-Hermann, Gispert, Suzana, Morales, Blas, Wingerter, Oliver, Del Turco, Domenico, Mülsch, Alexander, Nussbaum, Robert L, Müller, Klaus, Dröse, Stefan, Brandt, Ulrich, Deller, Thomas, Wirth, Brunhilde, Kudin, Alexei P, Kunz, Wolfram S, Auburger, Georg
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2007; Elsevier
• Subjects: Adult; Cell Line, Transformed; Electron Transport Complex I - genetics; Electron Transport Complex I - metabolism; Female; Fibroblasts; Glutathione; Glutathione - metabolism; Humans; Lipid Peroxidation - genetics; Lymphocytes - metabolism; Male; Malondialdehyde; Middle Aged; Mitochondria; Mitochondria - metabolism; MnSOD; Neurology; Oxidative stress; Oxidative Stress - physiology; PARK6; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; PINK1; Protein Kinases - genetics; Protein Kinases - metabolism; Superoxide Dismutase - metabolism; Superoxides - metabolism; Oxidative stress; Mitochondria; PINK1; MnSOD; Fibroblasts; PARK6; Malondialdehyde; Glutathione
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2006.10.007

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.