Autosomal recessive juvenile parkinsonism Cys212Tyr mutation in parkin renders lymphocytes susceptible to dopamine- and iron-mediated apoptosis.

Abstract

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.

• Authors: Marlene Jimenez Del Rio, Sonia Moreno, Gloria Garcia-Ospina, Omar Buritica, Carlos S Uribe, Francisco Lopera, Carlos Velez-Pardo
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 19 Issue 3 Pg. 324-30 (Mar 2004) ISSN: 0885-3185 [Print] United States
• PMID: 15022188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Movement Disorder Society

Chemical References

• Dipeptides
• NF-kappa B
• Transcription Factors
• cysteinyltyrosine
• Iron
• Ubiquitin-Protein Ligases
• parkin protein
• Dopamine

Topics

• Apoptosis (drug effects)
• DNA Mutational Analysis
• Dipeptides (genetics)
• Dopamine (metabolism)
• Female
• Humans
• Iron (pharmacology)
• Lymphocytes (metabolism)
• Male
• Membrane Potentials
• Middle Aged
• NF-kappa B (genetics)
• Parkinsonian Disorders (genetics, pathology)
• Point Mutation (genetics)
• Transcription Factors
• Ubiquitin-Protein Ligases (genetics)