Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease.
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.
Björkqvist
Maria
M
Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, BMC A10, Lund, Sweden. maria.bjorkqvist@med.lu.se
Petersén
Asa
A
Bacos
Karl
K
Isaacs
Jeremy
J
Norlén
Per
P
Gil
Joana
J
Popovic
Natalija
N
Sundler
Frank
F
Bates
Gillian P
GP
Tabrizi
Sarah J
SJ
Brundin
Patrik
P
Mulder
Hindrik
H
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000652:urine; D000328:Adult; D000818:Animals; D050218:Body Fat Distribution; D015519:Bone Density; D003345:Corticosterone / Q000097:blood* / Q000652:urine; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D007030:Hypothalamo-Hypophyseal System / Q000473:pathology* / Q000503:physiopathology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000473:pathology* / Q000503:physiopathology; D017448:Receptors, Dopamine D2 / Q000378:metabolism
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017448:Receptors, Dopamine D2; D000324:Adrenocorticotropic Hormone; D004298:Dopamine; D003345:Corticosterone; D006854:Hydrocortisone