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Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine

Petersén, Åsa LU ; Hansson, Oskar LU orcid ; Puschban, Zoe LU ; Sapp, Ellen ; Romero, Norma ; Castilho, Roger F. ; Sulzer, David ; Rice, Margaret ; DiFiglia, Marian and Przedborski, Serge , et al. (2001) In European Journal of Neuroscience 14(9). p.1425-1435
Abstract
Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa... (More)
Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N-methyl-d-aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cell death, Huntington's disease, oxidative stress, striatum
in
European Journal of Neuroscience
volume
14
issue
9
pages
1425 - 1435
publisher
Wiley-Blackwell
external identifiers
  • pmid:11722604
  • scopus:0035783947
ISSN
1460-9568
DOI
10.1046/j.0953-816x.2001.01765.x
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Psychiatry/Primary Care/Public Health (013240500), Translational Neuroendocrinology (013210010), Department of Experimental Medical Science (013210000)
id
9bb8559e-62cc-48c3-a791-ebabfd7ef72e (old id 1121150)
date added to LUP
2016-04-01 12:20:40
date last changed
2022-05-07 01:12:35
@article{9bb8559e-62cc-48c3-a791-ebabfd7ef72e,
  abstract     = {{Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid-induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA- and 6-hydroxydopamine-mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP-32) in R6/2 mice does not provide the resistance, as DA-induced striatal lesions are not reduced in size in DARPP-32 knockout mice. Neither DA receptor antagonists nor a N-methyl-d-aspartate (NMDA) receptor blocker reduce the size of DA-induced striatal lesions, suggesting that DA toxicity is not dependent upon DA- or NMDA receptor-mediated pathways. Moreover, superoxide dismutase-1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin-trap agent phenyl-butyl-tert-nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6-hydroxydopamine was also reduced in R6 mice, a yet-to-be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA-induced toxicity with age.}},
  author       = {{Petersén, Åsa and Hansson, Oskar and Puschban, Zoe and Sapp, Ellen and Romero, Norma and Castilho, Roger F. and Sulzer, David and Rice, Margaret and DiFiglia, Marian and Przedborski, Serge and Brundin, Patrik}},
  issn         = {{1460-9568}},
  keywords     = {{cell death; Huntington's disease; oxidative stress; striatum}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1425--1435}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{European Journal of Neuroscience}},
  title        = {{Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine}},
  url          = {{http://dx.doi.org/10.1046/j.0953-816x.2001.01765.x}},
  doi          = {{10.1046/j.0953-816x.2001.01765.x}},
  volume       = {{14}},
  year         = {{2001}},
}