title: Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine.
abstract: Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N-methyl-d-aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age.
authors.affiliation: Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sweden. Asa.Petersen@mphy.lu.se
authors.forename: A
authors.initials: A
authors.lastname: Petersén
authors.forename: O
authors.initials: O
authors.lastname: Hansson
authors.forename: Z
authors.initials: Z
authors.lastname: Puschban
authors.forename: E
authors.initials: E
authors.lastname: Sapp
authors.forename: N
authors.initials: N
authors.lastname: Romero
authors.forename: R F
authors.initials: RF
authors.lastname: Castilho
authors.forename: D
authors.initials: D
authors.lastname: Sulzer
authors.forename: M
authors.initials: M
authors.lastname: Rice
authors.forename: M
authors.initials: M
authors.lastname: DiFiglia
authors.forename: S
authors.initials: S
authors.lastname: Przedborski
authors.forename: P
authors.initials: P
authors.lastname: Brundin
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D004298:Dopamine / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005978:Glutathione / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009498:Neurotoxins / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics; D017378:Quinolinic Acid / Q000633:toxicity; D012183:Retrograde Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014527:Uric Acid / Q000378:metabolism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D010750:Phosphoproteins; C000606290:SOD1 protein, human; D014527:Uric Acid; D016627:Oxidopamine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D017378:Quinolinic Acid; D005978:Glutathione; D001205:Ascorbic Acid; D004298:Dopamine