Choosing an animal model for the study of Huntington's disease

Key Points

  • Animal models of Huntington's disease (HD), which have been established in species that range from worms, fruitflies, mice and rats to pigs, sheep and monkeys, have provided important insights into the pathogenesis of this disease.

  • Key distinguishing factors among animal models of HD are the genetic approach with which they were generated and the nature of the huntingtin (HTT) mutation that they carry.

  • The symptoms exhibited by each model largely reflect the genetic approach and transgene construct used to generate them.

  • Rodents are by far the most commonly used animals for modelling HD, with over 20 different models having been generated.

  • Different species of animals are better suited for modelling certain aspects of HD and for different applications. The choice of species and the particular model to use will therefore depend on the specific question of interest.

  • The goal of generating large animal models of HD should be pursued as certain challenges with regard to developing therapeutics for HD cannot be met in rodents and other small animals.

Abstract

Since the identification of the causative gene in Huntington's disease (HD), a number of animal models of this disorder have been developed. A frequently asked question is: which of these models most closely recapitulates the human disease? In this Review, we provide an overview of the currently available animal models of HD in the context of the clinical features of the disease. In doing so, we highlight their strengths and limitations for modelling specific symptoms of the disease. This should highlight the animal model that is best suited to address a particular question of interest and, ultimately, to expedite the discovery of treatments that will prevent or slow the progression of HD.

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Figure 1: Genetic attributes of animal models of HD.

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Acknowledgements

The authors are indebted to the Biomedical Research Council and the National University of Singapore for financial support (M.A.P. and M.R.H). M.A.P. is the recipient of the BC Innovation Council Ripples of Hope Award in Biotechnology & Entrepreneurship, and awards from the Canadian Institute of Health Research (CIHR) and the Michael Smith Foundation for Health Research (MSFHR). M.R.H. is supported by grants from the CIHR, the Huntington Society of Canada, the Huntington's Disease Society of America and the CHDI Foundation. M.R.H. is a Killam University Professor and holds a Canada Research Chair in Human Genetics.

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Glossary

Knock-in model

A genetic animal model in which the alteration comprises insertion of extragenomic DNA at a specific locus in the animal's genome.

UAS-GAL4 system

(Upstream activating sequence-GAL4 system). A bipartite enhancer system widely used in fruitfly studies that allows targeted expression of genes of interest in specific tissues.

Yeast artificial chromosome

(YAC). DNA vectors engineered to replicate in yeast and used to clone very large pieces of DNA.

Bacterial artificial chromosome

(BAC). DNA vectors engineered to replicate in bacteria and used to clone very large pieces of DNA.

Chorea

An irregular, jerky, dance-like involuntary movement that is characteristic of a number of movement disorders, including Huntington's disease.

Dystonia

Involuntary muscle contractions that can cause twisting and abnormal postures.

Bradykinesia

A slowness in the performance of voluntary movements.

Dysarthria

Speech abnormalities as a result of dysfunction of the motor component of speech production.

Dysphagia

A difficulty in swallowing.

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Pouladi, M., Morton, A. & Hayden, M. Choosing an animal model for the study of Huntington's disease. Nat Rev Neurosci 14, 708–721 (2013). https://doi.org/10.1038/nrn3570

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