Midbrain neuronal cultures from parkin mutant mice are resistant to nitric oxide-induced toxicity.
Nitric oxide (NO) is a modulator of differentiation and survival of dopamine (DA) neurons. NO may play a role in the pathogenesis of Parkinson's disease (PD) since its levels are increased in parkinsonian brains and it can nitrosylate and alter the function of key proteins involved in the pathogenesis of PD. NO producing neurons are spared in parkinsonian brains suggesting that toxicity by NO can be compensated. Furthermore, the neurotoxic or neurotrophic effects of NO on DA neurons depend on the balance between NO levels and the intracellular levels of glutathione (GSH). We have investigated the effects of NO-donating agents on midbrain neuronal cultures from parkin-deficient mice. Parkin mutations are the most common genetic deficit observed in hereditary parkinsonism. These mice have abnormal DA release and metabolism, increased production of free radicals and a compensatory elevation of GSH. Cultures from parkin knockout (PK-KO) mice were more resistant than those of wild type (WT) to the neurotoxicity by NO, and the difference of susceptibility applied equally to DA, GABA and total number of neurons, and to astrocytes. NO-induced cell death was mainly apoptotic and could be reduced by caspase inhibitors. Cultures from PK-KO had greater levels of GSH than WT and, after treatment with NO, greater levels of S-nitrosoglutathione. The differences in susceptibility disappear when the synthesis of GSH is inhibited or the GSH chelated with diethyl maleate. Our data show that, contrary to the expectations, and related to the enhanced production of GSH in parkin knockout mice, parkin-deficient dopamine neurons are less susceptible to toxicity by NO.
Solano
R M
RM
Department of Neurobiology, Hospital Ramón y Cajal, Ctra. de Colmenar, Km. 9, 28034 Madrid, Spain.
Menéndez
J
J
Casarejos
M J
MJ
Rodríguez-Navarro
J A
JA
García de Yébenes
J
J
Mena
M A
MA
D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D006834:Hydrazines / Q000633:toxicity*; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000633:toxicity*; D026422:S-Nitrosoglutathione / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D006834:Hydrazines; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D005978:Glutathione