PERSPECTIVE Putting the Brakes on Huntington Disease in a Mouse Experimental Model

Huntington disease (HD) is a hereditary neurodegenerative disorder that causes a progressively debilitating impact on movement, cognition, speech, and mood. It most commonly develops during adulthood and worsens over a 10–15-year period. The genetic basis of HD is an expan-sion of the (CAG)n trinucleotide repeat in the first exon of the HTT gene [1,2]. Although the function of the normal HTT protein is not well established, in-frame repeat expansion results in the accumulation of an abnormally long polyglutamine tract, which is believed to contribute to mutant protein toxicity and neural degeneration [3]. Consequently, CAG repeat length is inversely correlated with age of onset and severity of disease. Disease-size CAG repeats are prone to further lengthening, which leads to two distinct aspects of their instability: expansions during intergenerational transmissions and somatic expansions occurring throughout the life-time of an individual (Fig 1A). An outstanding question in the field is whether somatic expansions contribute to disease. The problem is that somatic expansions occur in the context of expressing an already toxic pro-tein, making it difficult to address this question. Two commonly discussed ideas are that (i) dis-ease arises with time because of expression of the toxic protein or RNA or that (ii) the onset o