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Accurate Huntington’s disease model reveals early phenotypes

Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by abnormal voluntary and involuntary movements, cognitive impairment and psychiatric disturbances, weight loss and cardiac failure. Onset typically occurs in mid-life. Currently there is no effective disease-modifying therapy and the disease relentlessly leads to death after ~10-15 years. HD is caused by an expansion >35 repeats of a polymorphic CAG repeat tract within exon 1 of the HTT gene, elongating a glutamine stretch at the amino-terminus of an ~350 kDa protein called huntingtin.

To better understand the HD pathogenic process scientists working with Vanessa Wheeler from the Center for Human Genetic Research at the General Hospital in Boston, Massachusetts have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. The mouse line HdhQ111 was analyzed in a systemic phenotypic screen in the German Mouse Clinic. To account for the fact that the disease progresses slowly, mice were analyzed between 10 and 46 weeks of age.

The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice. In the open field mutant mice stayed more time in the centre of the open field than wildtype littermates. This indicates decreased anxiety. Motor learning was impaired as well as olfactory discrimination. Furthermore the heterozygous knock-in mice showed coordination deficits, which were measured in the vertical pole descent.

The screen also provided evidence suggesting subtle cardiovascular, lung, and plasma metabolite alterations. The results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients.

As the authors point out, these data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

Hölter et al., A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice“, 2013, PLos One, Vol. 8(11). doi:10.1371/journal.pone.0080923