Autosomal recessive juvenile parkinsonism Cys212Tyr mutation in parkin renders lymphocytes susceptible to dopamine- and iron-mediated apoptosis.
Mutations in parkin are implicated in the pathogenesis of autosomal recessive juvenile parkinsonism (AR-JP) disease. We show that homozygote Cys212Tyr parkin mutation in AR-JP patients renders lymphocytes sensitive to dopamine, iron and hydrogen peroxide stimuli. Indeed, dopamine-induced apoptosis by four alternative mechanisms converging on caspase-3 activation and apoptotic morphology: (1) NF-kappaB-dependent pathway; mitochondrial dysfunction either by (2) H(2)O(2) or (3) hydroxyl exposure and (4) increase of unfolded-protein stress. We also demonstrate that 17beta-estradiol and testosterone prevent homozygote lymphocytes from oxidative stressors-evoked apoptosis. These results may contribute to understanding the relationship between genetic and environmental factors and iron in AR-JP.
Jimenez Del Rio
Marlene
M
School of Medicine, Department of Internal Medicine, Neurology Service, Neuroscience Research Programme, University of Antioquia, Medellin, Colombia. mdelrio@quimbaya.udea.edu.co
Moreno
Sonia
S
Garcia-Ospina
Gloria
G
Buritica
Omar
O
Uribe
Carlos S
CS
Lopera
Francisco
F
Velez-Pardo
Carlos
C
D017209:Apoptosis / Q000187:drug effects*; D004252:DNA Mutational Analysis; D004151:Dipeptides / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation / Q000235:genetics*; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D004151:Dipeptides; D016328:NF-kappa B; D014157:Transcription Factors; C072331:cysteinyltyrosine; D007501:Iron; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine