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Mutant huntingtin can paradoxically protect neurons from death

Zuchner, T and Brundin, Patrik LU (2008) In Cell Death and Differentiation 15(3). p.435-442
Abstract
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the... (More)
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
domain, neuroprotection, proline rich, NMDA, excitotoxicity, Huntington's disease, Huntingtin
in
Cell Death and Differentiation
volume
15
issue
3
pages
435 - 442
publisher
Nature Publishing Group
external identifiers
  • wos:000253239900002
  • scopus:39449105711
ISSN
1350-9047
DOI
10.1038/sj.cdd.4402261
language
English
LU publication?
yes
id
f836bba5-9e9d-467b-99c4-8280bce33bdd (old id 1196951)
date added to LUP
2008-09-10 12:47:16
date last changed
2017-01-01 04:24:39
@article{f836bba5-9e9d-467b-99c4-8280bce33bdd,
  abstract     = {Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.},
  author       = {Zuchner, T and Brundin, Patrik},
  issn         = {1350-9047},
  keyword      = {domain,neuroprotection,proline rich,NMDA,excitotoxicity,Huntington's disease,Huntingtin},
  language     = {eng},
  number       = {3},
  pages        = {435--442},
  publisher    = {Nature Publishing Group},
  series       = {Cell Death and Differentiation},
  title        = {Mutant huntingtin can paradoxically protect neurons from death},
  url          = {http://dx.doi.org/10.1038/sj.cdd.4402261},
  volume       = {15},
  year         = {2008},
}