Effect of overexpression of wild-type or mutant parkin on the cellular response induced by toxic insults.
Mutations in parkin are involved in some cases of autosomal recessive juvenile parkinsonism (AR-JP), but it is not known how they result in nigral cell death. We examined the effect of parkin overexpression on the response of cells to various insults. Wild-type and AR-JP-associated mutant parkins (Del3-5, T240R, and Q311X) were overexpressed in NT-2 and SK-N-MC cells. Overexpressed wild-type parkin delayed cell death induced by serum withdrawal, H(2)O(2), 1-methyl-4-phenylpyridinium (MPP(+)), or 4-hydroxy-2-trans-nonenal (HNE) but did not delay cell death caused by the proteasome inhibitor lactacystin. Increases in damage to proteins (protein carbonyls and 3-nitrotyrosine) were attenuated by wild-type parkin after serum withdrawal or exposure to H(2)O(2), MPP(+), or HNE but not after exposure to lactacystin. The mutant parkins (of all types) markedly accelerated cell death in response to all the insults, accompanied by increased levels of 8-hydroxyguanine, protein carbonyls, lipid peroxidation, and 3-nitrotyrosine and decreased levels of GSH. The viability loss induced by all the insults showed apoptotic features. The presence of parkin mutations in substantia nigra in Parkinson's disease may increase neuronal vulnerability to a range of toxic insults.
Hyun
Dong-Hoon
DH
Neurodegenerative Disease Research Centre, GKT School of Biomedical Sciences, King's College, London, United Kingdom.
Lee
Moonhee
M
Halliwell
Barry
B
Jenner
Peter
P
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004351:Drug Resistance / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D000447:Aldehydes; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D061988:Proteasome Inhibitors; C067713:lactacystin; C002744:3-nitrotyrosine; D018698:Glutamic Acid; D014443:Tyrosine; C024829:8-hydroxyguanine; D006147:Guanine; D006861:Hydrogen Peroxide; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal; D015655:1-Methyl-4-phenylpyridinium; D000111:Acetylcysteine