Advanced

Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration

Petersén, Åsa LU ; Larsen, Kristin E.; Behr, Gerald G.; Romero, Norma; Przedborski, Serge; Brundin, Patrik LU and Sulzer, David (2001) In Human Molecular Genetics 10(12). p.1243-1254
Abstract
Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved, To study intrinsic cellular mechanisms involved, To study Intrinsic to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine, The mutant neurons... (More)
Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved, To study intrinsic cellular mechanisms involved, To study Intrinsic to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine, The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes, The autophagic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this case by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
10
issue
12
pages
1243 - 1254
publisher
Oxford University Press
external identifiers
  • wos:000169400500002
ISSN
0964-6906
DOI
10.1093/hmg/10.12.1243
language
English
LU publication?
yes
id
cb420db3-5357-425d-9fa4-6aaa37f2b4d9 (old id 1119106)
date added to LUP
2008-07-09 11:26:40
date last changed
2016-04-15 20:08:09
@article{cb420db3-5357-425d-9fa4-6aaa37f2b4d9,
  abstract     = {Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved, To study intrinsic cellular mechanisms involved, To study Intrinsic to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine, The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes, The autophagic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this case by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD.},
  author       = {Petersén, Åsa and Larsen, Kristin E. and Behr, Gerald G. and Romero, Norma and Przedborski, Serge and Brundin, Patrik and Sulzer, David},
  issn         = {0964-6906},
  language     = {eng},
  number       = {12},
  pages        = {1243--1254},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration},
  url          = {http://dx.doi.org/10.1093/hmg/10.12.1243},
  volume       = {10},
  year         = {2001},
}