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Mouse models of Huntington disease: variations on a theme.

ABSTRACT: An accepted prerequisite for clinical trials of a compound in humans is the successful alleviation of the disease in animal models. For some diseases, however, successful translation of drug effects from mouse models to the bedside has been limited. One question is whether the current models accurately reproduce the human disease. Here, we examine the mouse models that are available for therapeutic testing in Huntington disease (HD), a late-onset neurodegenerative disorder for which there is no effective treatment. The current mouse models show different degrees of similarity to the human condition. Significant phenotypic differences are seen in mouse models that express either truncated or full-length human, or full-length mouse, mutant huntingtin (mHTT). These differences in phenotypic expression may be attributable to the influences of protein context, mouse strain and a difference in regulatory sequences between the mouse Htt and human HTT genes.

SUBMITTER: Ehrnhoefer DE

PROVIDER: S-EPMC2650190 | biostudies-literature | 2009 Mar-Apr

REPOSITORIES: biostudies-literature

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Mouse models of Huntington disease: variations on a theme.

Ehrnhoefer Dagmar E DE Butland Stefanie L SL Pouladi Mahmoud A MA Hayden Michael R MR

Disease models & mechanisms 20090301 3-4

An accepted prerequisite for clinical trials of a compound in humans is the successful alleviation of the disease in animal models. For some diseases, however, successful translation of drug effects from mouse models to the bedside has been limited. One question is whether the current models accurately reproduce the human disease. Here, we examine the mouse models that are available for therapeutic testing in Huntington disease (HD), a late-onset neurodegenerative disorder for which there is no ...[more]

PMID: 19259385

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Project description:Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology with selective loss of neurons expressing the neuropeptides orexin (hypocretin), oxytocin and vasopressin in human postmortem HD tissue. Hypothalamic changes in HD may have implications for early disease manifestations affecting the regulation of sleep, emotions and metabolism. The underlying mechanisms of selective vulnerability of certain neurons in HD are not fully understood, but excitotoxicity has been proposed to play a role. Further understanding of mechanisms rendering neurons sensitive to mutant huntingtin may reveal novel targets for therapeutic interventions. In the present study, we wanted to examine whether transgenic HD mice display altered sensitivity to excitotoxicity in the hypothalamus. We first assessed effects of hypothalamic injections of the excitotoxin quinolinic acid (QA) into wild-type (WT) mice. We show that neuronal populations expressing melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) display a dose-dependent sensitivity to QA. In contrast, neuronal populations expressing orexin, oxytocin, vasopressin as well as tyrosine hydroxylase in the A13 area are resistant to QA-induced toxicity. We demonstrate that the R6/2 transgenic mouse model expressing a short fragment of mutant HTT displays hypothalamic neuropathology with discrete loss of the neuronal populations expressing orexin, MCH, CART, and orexin at 12 weeks of age. The BACHD mouse model expressing full-length mutant HTT does not display any hypothalamic neuropathology at 2 months of age. There was no effect of hypothalamic injections of QA on the neuronal populations expressing orexin, MCH, CART or oxytocin in neither HD mouse model. In conclusion, we find no support for a role of excitotoxicity in the loss of hypothalamic neuronal populations in HD.

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Mouse models of Huntington disease: variations on a theme.

Publications

Mouse models of Huntington disease: variations on a theme.

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