Characterization of a rat model of Huntington's disease based on targeted expression of mutant huntingtin in the forebrain using adeno-associated viral vectors.
(2012) In European Journal of Neuroscience 36(6). p.2789-2800- Abstract
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (htt) gene. Neuropathology is most severe in the striatum and cerebral cortex. As mutant htt is ubiquitously expressed, it has not been possible to establish clear structure-to-function relationships for the clinical aspects. In the present study, we have injected recombinant adeno-associated viral vectors of serotype 5 (rAAV5) expressing an 853-amino-acid fragment of htt with either 79 (mutant) or 18 (wild-type) glutamines (Q) in the dorsal striatum of neonatal rats to achieve expression of htt in the forebrain. Rats were followed for 6 months and compared with control rats. Neuropathological assessment showed long-term... (More)
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (htt) gene. Neuropathology is most severe in the striatum and cerebral cortex. As mutant htt is ubiquitously expressed, it has not been possible to establish clear structure-to-function relationships for the clinical aspects. In the present study, we have injected recombinant adeno-associated viral vectors of serotype 5 (rAAV5) expressing an 853-amino-acid fragment of htt with either 79 (mutant) or 18 (wild-type) glutamines (Q) in the dorsal striatum of neonatal rats to achieve expression of htt in the forebrain. Rats were followed for 6 months and compared with control rats. Neuropathological assessment showed long-term expression of the green fluorescent protein (GFP) transgene (used as a marker protein) and accumulation of htt inclusions in the cerebral cortex with the rAAV5-htt-79Q vectors. We estimated that around 10% of NeuN-positive cells in the cerebral cortex and 2% of DARPP-32 neurons in the striatum were targeted with the GFP-expressing vector. Formation of intracellular htt inclusions was not associated with neuronal loss, gliosis or microglia activation and did not lead to altered motor activity or changes in body weight. However, the same mutant htt vector caused orexin loss in the hypothalamus - another area known to be affected in HD. In conclusion, our results demonstrate that widespread forebrain expression of mutant htt can be achieved using rAAV5-vectors and suggest that this technique can be further explored to study region-specific effects of mutant htt or other disease-causing genes in the brain. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2859033
- author
- Gabery, Sanaz LU ; Sajjad, Muhammad U ; Hult Lundh, Sofia LU ; Soylu, Rana LU ; Kirik, Deniz LU and Petersén, Åsa LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- European Journal of Neuroscience
- volume
- 36
- issue
- 6
- pages
- 2789 - 2800
- publisher
- Wiley-Blackwell
- external identifiers
-
- wos:000308941000008
- pmid:22731249
- scopus:84866421220
- pmid:22731249
- ISSN
- 1460-9568
- DOI
- 10.1111/j.1460-9568.2012.08193.x
- language
- English
- LU publication?
- yes
- id
- e741d576-9f16-4417-a0ed-689f51e994c5 (old id 2859033)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/22731249?dopt=Abstract
- date added to LUP
- 2016-04-04 08:16:51
- date last changed
- 2022-01-29 03:16:03
@article{e741d576-9f16-4417-a0ed-689f51e994c5,
abstract = {{Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (htt) gene. Neuropathology is most severe in the striatum and cerebral cortex. As mutant htt is ubiquitously expressed, it has not been possible to establish clear structure-to-function relationships for the clinical aspects. In the present study, we have injected recombinant adeno-associated viral vectors of serotype 5 (rAAV5) expressing an 853-amino-acid fragment of htt with either 79 (mutant) or 18 (wild-type) glutamines (Q) in the dorsal striatum of neonatal rats to achieve expression of htt in the forebrain. Rats were followed for 6 months and compared with control rats. Neuropathological assessment showed long-term expression of the green fluorescent protein (GFP) transgene (used as a marker protein) and accumulation of htt inclusions in the cerebral cortex with the rAAV5-htt-79Q vectors. We estimated that around 10% of NeuN-positive cells in the cerebral cortex and 2% of DARPP-32 neurons in the striatum were targeted with the GFP-expressing vector. Formation of intracellular htt inclusions was not associated with neuronal loss, gliosis or microglia activation and did not lead to altered motor activity or changes in body weight. However, the same mutant htt vector caused orexin loss in the hypothalamus - another area known to be affected in HD. In conclusion, our results demonstrate that widespread forebrain expression of mutant htt can be achieved using rAAV5-vectors and suggest that this technique can be further explored to study region-specific effects of mutant htt or other disease-causing genes in the brain.}},
author = {{Gabery, Sanaz and Sajjad, Muhammad U and Hult Lundh, Sofia and Soylu, Rana and Kirik, Deniz and Petersén, Åsa}},
issn = {{1460-9568}},
language = {{eng}},
number = {{6}},
pages = {{2789--2800}},
publisher = {{Wiley-Blackwell}},
series = {{European Journal of Neuroscience}},
title = {{Characterization of a rat model of Huntington's disease based on targeted expression of mutant huntingtin in the forebrain using adeno-associated viral vectors.}},
url = {{http://dx.doi.org/10.1111/j.1460-9568.2012.08193.x}},
doi = {{10.1111/j.1460-9568.2012.08193.x}},
volume = {{36}},
year = {{2012}},
}