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Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length

Hansson, Oskar LU ; Castilho, Roger F; Korhonen, Laura; Lindholm, Dan; Bates, Gillian P and Brundin, Patrik LU (2001) In Journal of Neurochemistry 78(4). p.694-703
Abstract
Transgenic Huntington's disease (HD) mice, expressing exon 1 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 HD mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HD 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... (More)
Transgenic Huntington's disease (HD) mice, expressing exon 1 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 HD mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HD 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 CAG 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 HD 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 HD 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
transgenic mouse, N-methyl-d-aspartate, Huntington's disease, malonate, excitotoxicity, cell death
in
Journal of Neurochemistry
volume
78
issue
4
pages
694 - 703
publisher
Wiley-Blackwell
external identifiers
  • pmid:11520890
  • scopus:0034889544
ISSN
1471-4159
DOI
10.1046/j.1471-4159.2001.00482.x
language
English
LU publication?
yes
id
b0416875-6c8a-4314-9fe7-ce1c0f7c9401 (old id 1121160)
date added to LUP
2008-08-27 14:02:57
date last changed
2018-05-29 09:25:15
@article{b0416875-6c8a-4314-9fe7-ce1c0f7c9401,
  abstract     = {Transgenic Huntington's disease (HD) mice, expressing exon 1 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 HD mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HD 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 CAG 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 HD 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 HD 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.},
  author       = {Hansson, Oskar and Castilho, Roger F and Korhonen, Laura and Lindholm, Dan and Bates, Gillian P and Brundin, Patrik},
  issn         = {1471-4159},
  keyword      = {transgenic mouse,N-methyl-d-aspartate,Huntington's disease,malonate,excitotoxicity,cell death},
  language     = {eng},
  number       = {4},
  pages        = {694--703},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length},
  url          = {http://dx.doi.org/10.1046/j.1471-4159.2001.00482.x},
  volume       = {78},
  year         = {2001},
}