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Partial resistance ...
Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length
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- Hansson, Oskar (author)
- Lund University,Lunds universitet,Institutionen för kliniska vetenskaper, Malmö,Medicinska fakulteten,Department of Clinical Sciences, Malmö,Faculty of Medicine,Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Lund, Sweden
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- Castilho, Roger F. (author)
- Department of Clinical Pathology, School of Medical Sciences, State University of Campinas, Campinas, Brazil
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- Korhonen, Laura, 1974- (author)
- Linköpings universitet,Centrum för social och affektiv neurovetenskap,Medicinska fakulteten,Region Östergötland, Barn- och ungdomspsykiatriska kliniken,Department of Neuroscience, Neurobiology, Uppsala University, Uppsala, Sweden
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- Lindholm, Dan (author)
- Department of Neuroscience, Neurobiology, Uppsala University, Uppsala, Sweden
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- Bates, Gillian P. (author)
- Medical and Molecular Genetics, GKT School of Medicine, London, UK
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- Brundin, Patrik (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine,Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Lund, Sweden
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(creator_code:org_t)
- 2001-12-20
- 2001
- English.
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In: Journal of Neurochemistry. - Lund 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, England. : BLACKWELL SCIENCE LTD. - 0022-3042 .- 1471-4159. ; 78:4, s. 694-703
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Abstract
Subject headings
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- 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 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- cell death
- excitotoxicity
- Huntington's disease
- malonate
- N-methyl-D-aspartate
- transgenic mouse
- transgenic mouse
- N-methyl-d-aspartate
- Huntington's disease
- malonate
- excitotoxicity
- cell death
Publication and Content Type
- ref (subject category)
- art (subject category)
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