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dc.contributor.CRUESPUniversidade Estadual de Campinaspt_BR
dc.typeArtigo de periódicopt_BR
dc.titlePartial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat lengthpt_BR
dc.contributor.authorHansson, Opt_BR
dc.contributor.authorCastilho, RFpt_BR
dc.contributor.authorKorhonen, Lpt_BR
dc.contributor.authorLindholm, Dpt_BR
dc.contributor.authorBates, GPpt_BR
dc.contributor.authorBrundin, Ppt_BR
unicamp.authorLund Univ, Sect Neuronal Survival, Wallenberg Neurosci Ctr, Dept Physiol Sci, S-22184 Lund, Sweden State Univ Campinas, Sch Med Sci, Dept Clin Pathol, Campinas, SP, Brazil Univ Uppsala, Dept Neurosci, Uppsala, Sweden GKT, Sch Med, London, Englandpt_BR
dc.subjectcell deathpt_BR
dc.subjectexcitotoxicitypt_BR
dc.subjectHuntington's diseasept_BR
dc.subjectmalonatept_BR
dc.subjectN-methyl-D-aspartatept_BR
dc.subjecttransgenic mousept_BR
dc.subject.wosNeuronal Intranuclear Inclusionspt_BR
dc.subject.wosNmda Receptor Activationpt_BR
dc.subject.wos3-nitropropionic Acidpt_BR
dc.subject.wosRat Striatumpt_BR
dc.subject.wosSuccinate-dehydrogenasept_BR
dc.subject.wosInhibitor Malonatept_BR
dc.subject.wosMicept_BR
dc.subject.wosMutationpt_BR
dc.subject.wosLesionspt_BR
dc.subject.wosEnergypt_BR
dc.description.abstractTransgenic, Huntington's disease (HD) mice, expressing exon I of the HD gene with an expanded CAG repeat, are totally resistant to striatal, lesion induced by excessive NMDA receptor activation. We now show that striatal lesions induced by the mitochondrial toxin malonate are reduced by 70-80% in transgenic HD mice compared with wild-type littermate controls. This occurred in 6- and 12-week-old HID mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HID mice with 115 CAG repeats (line R6/1). Therefore, we show for the first time that the resistance to neurotoxin in transgenic HD mice is dependent on both the CAG repeat length and the age of the mice. Importantly, most HD patients develop symptoms in adulthood and exhibit an inverse relationship between GAG repeat length and age of onset. Transgenic mice expressing a normal CAG repeat (18 CAG) were not resistant to malonate. Although endogenous glutamate release has been implicated in malonate-induced cell death, glutamate release from striatal synaptosomes was not decreased in HID mice. Malonate-induced striatal cell death was reduced by 50-60% in wild-type mice when they were treated with either the NMDA receptor antagonist MK-801 or the caspase inhibitor zVAD-fmk. These two compounds did not reduce lesion size in transgenic R6/1 mice. This might suggest that NMDA receptor- and caspase-mediated cell death pathways are inhibited and that the limited malonate-induced cell death still occurring in HID mice is independent of these pathways. There were no changes in striatal levels of the two anti cell death proteins Bcl-X-L and X-linked Inhibitor of apoptosis protein (XIAP), before or after the lesion in transgenic HD mice. We propose that mutant huntingtin causes a sublethal grade of metabolic stress which is CAG repeat length-dependent and results in up-regulation over time of cellular defense mechanisms against impaired energy metabolism and excitotoxicity.pt
dc.relation.ispartofJournal Of Neurochemistrypt_BR
dc.relation.ispartofabbreviationJ. Neurochem.pt_BR
dc.publisher.cityOxfordpt_BR
dc.publisher.countryInglaterrapt_BR
dc.publisherBlackwell Science Ltdpt_BR
dc.date.issued2001pt_BR
dc.date.monthofcirculationAUGpt_BR
dc.identifier.citationJournal Of Neurochemistry. Blackwell Science Ltd, v. 78, n. 4, n. 694, n. 703, 2001.pt_BR
dc.language.isoenpt_BR
dc.description.volume78pt_BR
dc.description.issuenumber4pt_BR
dc.description.firstpage694pt_BR
dc.description.lastpage703pt_BR
dc.rightsfechadopt_BR
dc.sourceWeb of Sciencept_BR
dc.identifier.issn0022-3042pt_BR
dc.identifier.wosidWOS:000170494100004pt_BR
dc.identifier.doi10.1046/j.1471-4159.2001.00482.xpt_BR
dc.date.available2014-11-16T18:22:51Z
dc.date.available2015-11-26T17:26:11Z-
dc.date.accessioned2014-11-16T18:22:51Z
dc.date.accessioned2015-11-26T17:26:11Z-
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dc.description.provenanceMade available in DSpace on 2015-11-26T17:26:11Z (GMT). No. of bitstreams: 2 WOS000170494100004.pdf: 628580 bytes, checksum: 1df510f921f221dee947cf0d9947d8cd (MD5) WOS000170494100004.pdf.txt: 50826 bytes, checksum: c41dad9522c123fb7f506ebd863b76a1 (MD5) Previous issue date: 2001en
dc.identifier.urihttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/59088pt_BR
dc.identifier.urihttp://www.repositorio.unicamp.br/handle/REPOSIP/59088
dc.identifier.urihttp://repositorio.unicamp.br/jspui/handle/REPOSIP/59088-
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