Human Molecular Genetics Advance Access published online on April 13, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl094
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1 Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A10, Lund, Sweden; Unit of Molecular Metabolism, Division of Diabetes, Metabolism, and Endocrinology, Department of Experimental Medical Science, BMC C11, Lund, Sweden
* To whom correspondence should be addressed. Huntington's disease (HD) is characterised by a triad of motor, psychiatric, and cognitive symptoms. While 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 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.
Received December 21, 2005
Revised March 30, 2006
Accepted March 30, 2006
Article
Progressive Alterations in the Hypothalamic-Pituitary-Adrenal Axis in the R6/2 Transgenic Mouse Model of Huntington's disease
Maria Björkqvist 1 *,
Åsa Petersén 2,
Karl Bacos 3,
Jeremy Isaacs 4,
Per Norlén 5,
Joana Gil 2,
Natalija Popovic 2,
Frank Sundler 6,
Gillian P. Bates 7,
Sarah J. Tabrizi 4,
Patrik Brundin 2,
and
Hindrik Mulder 3
2 Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A10, Lund, Sweden
3 Unit of Molecular Metabolism, Division of Diabetes, Metabolism, and Endocrinology, Department of Experimental Medical Science, BMC C11, Lund, Sweden
4 Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG
5 Unit of Clinical and Experimental Pharmacology, Department of Laboratory Medicine, Lund University Hospital, Lund, Sweden
6 Unit of Neuroendocrine Cell Biology, Division of Diabetes, Metabolism, and Endocrinology, Department of Experimental Medical Science, BMC F10, Lund, Sweden
7 Department of Medical and Molecular Genetics, GKT School of Medicine, King's College, Guy's Hospital, London, UK
Maria Björkqvist, E-mail: maria.bjorkqvist{at}med.lu.se
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