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Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin.

Pouladi, Mahmoud A; Graham, Rona K; Karasinska, Joanna M; Xie, Yuanyun; Santos, Rachelle Dar; Petersén, Åsa LU and Hayden, Michael R (2009) In Brain 132. p.919-932
Abstract
Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in... (More)
Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in clinical Huntington disease, we chose to assess whether a model for Huntington disease not subject to environmental stressors, namely the YAC mouse model of Huntington disease, displays a depressive phenotype. Indeed, the YAC transgenic mice recapitulate the early depressive phenotype of Huntington disease as assessed by the Porsolt forced swim test as well as the sucrose intake test as a measure of anhedonia. The YAC model mirrors clinical Huntington disease in that there were no effects of CAG repeat length or disease duration on the depressive phenotype. The depressive phenotype was completely rescued in YAC transgenic animals expressing a variant of mutant huntingtin that is resistant to cleavage at amino acid 586 suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on this aspect of the disease. In conclusion, our study provides strong support for a primary neurobiological basis for depression in Huntington disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Brain
volume
132
pages
919 - 932
publisher
Oxford University Press
external identifiers
  • wos:000265269600016
  • pmid:19224899
  • scopus:65249132310
ISSN
1460-2156
DOI
10.1093/brain/awp006
language
English
LU publication?
yes
id
1dd1d1e7-9b2b-4d3d-9ea8-c1ed67f5b60a (old id 1302459)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19224899?dopt=Abstract
date added to LUP
2009-03-03 11:49:31
date last changed
2017-12-10 04:44:33
@article{1dd1d1e7-9b2b-4d3d-9ea8-c1ed67f5b60a,
  abstract     = {Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in clinical Huntington disease, we chose to assess whether a model for Huntington disease not subject to environmental stressors, namely the YAC mouse model of Huntington disease, displays a depressive phenotype. Indeed, the YAC transgenic mice recapitulate the early depressive phenotype of Huntington disease as assessed by the Porsolt forced swim test as well as the sucrose intake test as a measure of anhedonia. The YAC model mirrors clinical Huntington disease in that there were no effects of CAG repeat length or disease duration on the depressive phenotype. The depressive phenotype was completely rescued in YAC transgenic animals expressing a variant of mutant huntingtin that is resistant to cleavage at amino acid 586 suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on this aspect of the disease. In conclusion, our study provides strong support for a primary neurobiological basis for depression in Huntington disease.},
  author       = {Pouladi, Mahmoud A and Graham, Rona K and Karasinska, Joanna M and Xie, Yuanyun and Santos, Rachelle Dar and Petersén, Åsa and Hayden, Michael R},
  issn         = {1460-2156},
  language     = {eng},
  pages        = {919--932},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin.},
  url          = {http://dx.doi.org/10.1093/brain/awp006},
  volume       = {132},
  year         = {2009},
}