Human Molecular Genetics Advance Access originally published online on September 20, 2006
Human Molecular Genetics 2006 15(21):3119-3131; doi:10.1093/hmg/ddl252
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Cholinergic neuronal defect without cell loss in Huntington's disease
1 Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden, 2 Department of Neurology, LUMC, 2300 Leiden, The Netherlands, 3 Department of Neurology, and 4 Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA, 5 Department of Clinical Science, Lund Division V, Pathology, University Hospital, 221 84 Lund, Sweden and 6 Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, The University of Auckland, 92019 Auckland, New Zealand
* To whom correspondence should be addressed. Tel: +46 462220525; Fax: +46 462220531. Email: jia-yi.li{at}med.lu.se
Received June 29, 2006; Revised August 30, 2006; Accepted September 7, 2006
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Hayashi, H. Arima, N. Ozaki, Y. Morishita, M. Hiroi, N. Ozaki, H. Nagasaki, N. Kinoshita, M. Ueda, A. Shiota, et al. Progressive polyuria without vasopressin neuron loss in a mouse model for familial neurohypophysial diabetes insipidus Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1641 - R1649. [Abstract] [Full Text] [PDF]
|
|