Neuronal transfer of the human Cu/Zn superoxide dismutase gene increases the resistance of dopaminergic neurons to 6-hydroxydopamine.
Several mechanisms are thought to be involved in the progressive decline in neurons of the substantia nigra pars compacta (SNpc) that leads to Parkinson's disease (PD). Neurotoxin 6-hydroxydopamine (6-OHDA), which induces parkinsonian symptoms in experimental animals, is thought to be formed endogenously in patients with PD through dopamine (DA) oxidation and may cause dopaminergic cell death via a free radical mechanism. We therefore investigated protection against 6-OHDA by inhibiting oxidative stress using a gene transfer strategy. We overexpressed the antioxidative Cu/Zn-superoxide dismutase (SOD1) enzyme in primary culture dopaminergic cells by infection with an adenovirus carrying the human SOD1 gene (Ad-hSOD1). Survival of the dopaminergic cells exposed to 6-OHDA was 50% higher among the SOD1-producing cells than the cells infected with control adenoviruses. In contrast, no significant increased survival of (6-OHDA)-treated dopaminergic cells was observed when they were infected with an adenovirus expressing the H(2) O(2) -scavenging glutathione peroxidase (GPx) enzyme. These results underline the major contribution of superoxide in the dopaminergic cell death process induced by 6-OHDA in primary cultures. Overall, this study demonstrates that the survival of the dopaminergic neurons can be highly increased by the adenoviral gene transfer of SOD1. An antioxidant gene transfer strategy using viral vectors expressing SOD1 is therefore potentially beneficial for protecting dopaminergic neurons in PD.
Barkats
Martine
M
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS UMR C9923, Hôpital de la Pitié-Salpétrière, 83 boulevard de l'Hôpital, 75013 Paris, France.
Millecamps
Stéphanie
S
Bilang-Bleuel
Alicia
A
Mallet
Jacques
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D018014:Gene Transfer Techniques; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D016627:Oxidopamine; D005979:Glutathione Peroxidase; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D004298:Dopamine