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Titolo:
Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length
Autore:
Hansson, O; Castilho, RF; Korhonen, L; Lindholm, D; Bates, GP; Brundin, P;
Indirizzi:
Lund Univ, Sect Neuronal Survival, Wallenberg Neurosci Ctr, Dept Physiol Sci, S-22184 Lund, Sweden Lund Univ Lund Sweden S-22184 tr, Dept Physiol Sci, S-22184 Lund, Sweden State Univ Campinas, Sch Med Sci, Dept Clin Pathol, Campinas, SP, Brazil State Univ Campinas Campinas SP Brazil Clin Pathol, Campinas, SP, Brazil Univ Uppsala, Dept Neurosci, Uppsala, Sweden Univ Uppsala Uppsala Sweden niv Uppsala, Dept Neurosci, Uppsala, Sweden GKT, Sch Med, London, England GKT London EnglandGKT, Sch Med, London, England
Titolo Testata:
JOURNAL OF NEUROCHEMISTRY
fascicolo: 4, volume: 78, anno: 2001,
pagine: 694 - 703
SICI:
0022-3042(200108)78:4<694:PRTMSC>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEURONAL INTRANUCLEAR INCLUSIONS; NMDA RECEPTOR ACTIVATION; 3-NITROPROPIONIC ACID; RAT STRIATUM; SUCCINATE-DEHYDROGENASE; INHIBITOR MALONATE; MICE; MUTATION; LESIONS; ENERGY;
Keywords:
cell death; excitotoxicity; Huntington's disease; malonate; N-methyl-D-aspartate; transgenic mouse;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Hansson, O Lund Univ, Sect Neuronal Survival, Wallenberg Neurosci Ctr, Dept Physiol Sci, BMC A10, S-22184 Lund, Sweden Lund Univ BMC A10 Lund SwedenS-22184 10, S-22184 Lund, Sweden
Citazione:
O. Hansson et al., "Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length", J NEUROCHEM, 78(4), 2001, pp. 694-703

Abstract

Transgenic, 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 ofthe 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 resistantto 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 NMDAreceptor 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 HIDmice 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 ofapoptosis 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/04/20 alle ore 20:14:41