Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease

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Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease. / Björkqvist, Maria; Petersén, Åsa; Bacos, Karl; Isaacs, J; Norlén, Per; Gil, Joana; Popovic, Natalija; Sundler, Frank; Bates, GP; Tabrizi, SJ; Brundin, Patrik; Mulder, Hindrik.

In: Human Molecular Genetics, Vol. 15, No. 10, 2006, p. 1713-1721.

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Björkqvist, Maria ; Petersén, Åsa ; Bacos, Karl ; Isaacs, J ; Norlén, Per ; Gil, Joana ; Popovic, Natalija ; Sundler, Frank ; Bates, GP ; Tabrizi, SJ ; Brundin, Patrik ; Mulder, Hindrik. / Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease. In: Human Molecular Genetics. 2006 ; Vol. 15, No. 10. pp. 1713-1721.

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TY - JOUR

T1 - Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease

AU - Björkqvist, Maria

AU - Petersén, Åsa

AU - Bacos, Karl

AU - Isaacs, J

AU - Norlén, Per

AU - Gil, Joana

AU - Popovic, Natalija

AU - Sundler, Frank

AU - Bates, GP

AU - Tabrizi, SJ

AU - Brundin, Patrik

AU - Mulder, Hindrik

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddl094

DO - 10.1093/hmg/ddl094

M3 - Article

VL - 15

SP - 1713

EP - 1721

JO - Human Molecular Genetics

T2 - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 10

ER -