Review
Mouse models of Huntington's disease

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Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In 1993 the mutation that causes HD was identified as an unstable expansion of CAG repeats in the IT15 gene. Since then one of the most important advances in HD research has been the generation of various mouse models that enable the exploration of early pathological, molecular and cellular abnormalities produced by the mutation. In addition, these models have made it possible to test different pharmacological approaches to delay the onset or slow the progression of HD. In this article, insights gained from mouse models towards the understanding of HD and the design of new therapeutic strategies are discussed.

Section snippets

Knockout mice

Soon after the discovery of the gene mutation that causes HD, it was found that homozygous knockout of this gene in mice was embryonic lethal 8, 9, 10, which contrasts with the late onset of the disease in humans. Thus, these early mouse models are not good models of the disease but they do indicate that huntingtin has an essential role in embryonic development. Furthermore, mutant huntingtin can rescue the knockout phenotype, which indicates that the effect of the mutation is not primarily due

Transgenic mouse models of HD

The general characteristics and a summary of findings in transgenic mice are presented in Table 1 and Table 2.

Knock-in models of HD

In theory, knock-in models (Table 3) should be optimal to reproduce human pathology and test prospective treatments because they are the most faithful reproduction of the disease genotype. In practice, these models were disappointing initially because the mice showed either no behavioral phenotypes 11, 41 or anomalies that apparently did not involve movement disorders [42]. However, this initial disappointment has been dispelled by closer analysis and generation of additional models 43, 44. It

Curing HD: clues from mouse models

One striking observation that derives from comparing the mouse models described earlier is that mice expressing full-length mutated proteins have a less aggressive course of disease than mice that express a truncated form. This agrees with observations made in cell-based assays where long fragments of mutant huntingtin are less toxic to cells than short, N-terminal fragments containing the same number of CAG repeats [48]. This observation strongly indicates that specific proteolysis of

Concluding remarks

Eight years after the identification of the gene responsible for HD [3], the disease remains untreatable. However, major progress has been made in our understanding of HD and several avenues for rational therapeutic approaches are starting to open. Although work in vitro has contributed greatly, analysis of mouse models has been crucial to this progress because of the opportunity they provide to examine pathological, cellular and molecular events that occur at the early stages of the disease.

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