Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6.
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.
Hoepken
Hans-Hermann
HH
Section for Molecular Neurogenetics, Clinic for Neurology, University Hospital, Theodor Stern Kai 7, 60590 Frankfurt/M., Germany.
Gispert
Suzana
S
Morales
Blas
B
Wingerter
Oliver
O
Del Turco
Domenico
D
Mülsch
Alexander
A
Nussbaum
Robert L
RL
Müller
Klaus
K
Dröse
Stefan
S
Brandt
Ulrich
U
Deller
Thomas
T
Wirth
Brunhilde
B
Kudin
Alexei P
AP
Kunz
Wolfram S
WS
Auburger
Georg
G
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
D042967:Electron Transport Complex I; D005978:Glutathione; D011494:Protein Kinases; D013482:Superoxide Dismutase; D013481:Superoxides; D000099202:PTEN-Induced Putative Kinase