Human Molecular Genetics Advance Access originally published online on April 13, 2006
Human Molecular Genetics 2006 15(10):1713-1721; doi:10.1093/hmg/ddl094
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease
1Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A10, Lund, Sweden, 2Unit of Molecular Metabolism, Division of Diabetes, Metabolism, and Endocrinology, Department of Experimental Medical Science, BMC C11, SE-221 84 Lund, Sweden, 3Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1 N 3BG, UK, 4Unit of Clinical and Experimental Pharmacology, Department of Laboratory Medicine, Lund University Hospital, Lund, Sweden, 5Unit of Neuroendocrine Cell Biology, Division of Diabetes, Metabolism, and Endocrinology, Department of Experimental Medical Science, BMC F10, Lund, Sweden and 6Department of Medical and Molecular Genetics, GKT School of Medicine, King's College, Guy's Hospital, London, UK
* To whom correspondence should be addressed. Tel: +46 462229796; Email: maria.bjorkqvist{at}med.lu.se
Received December 21, 2005; Accepted March 30, 2006
Huntington's disease (HD) is characterized by a triad of motor, psychiatric and cognitive symptoms. Although many of these symptoms are likely to be related to central nervous system pathology, others may be due to changes in peripheral tissues. The R6/2 mouse, a transgenic model of HD expressing exon 1 of the human HD gene, develops progressive alterations in the hypothalamic-pituitary-adrenal axis, reminiscent of a Cushing-like syndrome. We observed muscular atrophy, reduced bone mineral density, abdominal fat accumulation and insulin resistance in the mice. All these changes could be consequences of increased glucocorticoid levels. Indeed, hypertrophy of the adrenal cortex and a progressive increase in serum and urine corticosterone levels were found in R6/2 mice. In addition, the intermediate pituitary lobe was markedly enlarged and circulating adreno-corticotrophic hormone (ACTH) increased. Under normal conditions dopamine represses the ACTH expression. In the R6/2 mice, however, the expression of pituitary dopamine D2 receptors was reduced by half, possibly explaining the increase in ACTH. Urinary samples from 82 HD patients and 68 control subjects were analysed for cortisol: in accord with the observations in the R6/2 mice, urinary cortisol increased in parallel with disease progression. This progressive increase in cortisol may contribute to the clinical symptoms, such as muscular wasting, mood changes and some of the cognitive deficits that occur in HD.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. J. Bode, M. Stephan, H. Suhling, R. Pabst, R. H. Straub, K. A. Raber, M. Bonin, H. P. Nguyen, O. Riess, A. Bauer, et al. Sex differences in a transgenic rat model of Huntington's disease: decreased 17{beta}-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males Hum. Mol. Genet., September 1, 2008; 17(17): 2595 - 2609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bjorkqvist, E. J. Wild, J. Thiele, A. Silvestroni, R. Andre, N. Lahiri, E. Raibon, R. V. Lee, C. L. Benn, D. Soulet, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease J. Exp. Med., August 4, 2008; 205(8): 1869 - 1877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Smith, H. Chung, S. Rundquist, M. L.C. Maat-Schieman, L. Colgan, E. Englund, Y.-J. Liu, R. A.C. Roos, R. L.M. Faull, P. Brundin, et al. Cholinergic neuronal defect without cell loss in Huntington's disease Hum. Mol. Genet., November 1, 2006; 15(21): 3119 - 3131. [Abstract] [Full Text] [PDF]
|
|