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Cholinergic neuronal defect without cell loss in Huntington's disease.

Smith, Ruben LU ; Chung, Hinfan ; Rundquist, Sara ; Maat-Schieman, Marion L C ; Colgan, Lesley ; Englund, Elisabet LU ; Liu, Yong-Jian ; Roos, Raymund A C ; Faull, Richard L M and Brundin, Patrik LU , et al. (2006) In Human Molecular Genetics 15(21). p.3119-3131
Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein... (More)
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
15
issue
21
pages
3119 - 3131
publisher
Oxford University Press
external identifiers
  • wos:000241430000004
  • scopus:33750201279
ISSN
0964-6906
DOI
10.1093/hmg/ddl252
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: Neuronal Survival (013212041), Pathology, (Lund) (013030000)
id
fd1dc9e3-05ec-4d66-b3b5-dd8c692fcdd6 (old id 160909)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16987871&dopt=Abstract
date added to LUP
2016-04-01 12:05:13
date last changed
2020-10-07 02:26:41
@article{fd1dc9e3-05ec-4d66-b3b5-dd8c692fcdd6,
  abstract     = {Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingtin (IT15) gene. The striatum is one of the regions most affected by neurodegeneration, resulting in the loss of the medium-sized spiny neurons. Traditionally, the large cholinergic striatal interneurons are believed to be spared. Recent studies demonstrate that neuronal dysfunction without cell death also plays an important role in early and mid-stages of the disease. Here, we report that cholinergic transmission is affected in a HD transgenic mouse model (R6/1) and in tissues from HD patients. Stereological analysis shows no loss of cholinergic neurons in the striatum or septum in R6/1 mice. In contrast, the levels of mRNA and protein for vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) are decreased in the striatum and cortex, and acetylcholine esterase activity is lowered in the striatum of R6/1 mice already at young ages. Accordingly, VAChT is also reduced in striatal tissue from patients with HD. The decrease of VAChT in the patient samples studied is restricted to the striatum and does not occur in the hippocampus or the spinal cord. The expression and localization of REST/NRSF, a transcriptional regulator for the VAChT and ChAT genes, are not altered in cholinergic neurons. We show that the R6/1 mice exhibit severe deficits in learning and reference memory. Taken together, our data show that the cholinergic system is dysfunctional in R6/1 and HD patients. Consequently, they provide a rationale for testing of pro-cholinergic drugs in this disease.},
  author       = {Smith, Ruben and Chung, Hinfan and Rundquist, Sara and Maat-Schieman, Marion L C and Colgan, Lesley and Englund, Elisabet and Liu, Yong-Jian and Roos, Raymund A C and Faull, Richard L M and Brundin, Patrik and Li, Jia-Yi},
  issn         = {0964-6906},
  language     = {eng},
  number       = {21},
  pages        = {3119--3131},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Cholinergic neuronal defect without cell loss in Huntington's disease.},
  url          = {http://dx.doi.org/10.1093/hmg/ddl252},
  doi          = {10.1093/hmg/ddl252},
  volume       = {15},
  year         = {2006},
}