Trends in Genetics
Volume 18, Issue 4, 1 April 2002, Pages 202-209
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Review
Lessons from animal models of Huntington's disease

https://doi.org/10.1016/S0168-9525(01)02625-7Get rights and content

Abstract

Huntington's disease (HD) is an autosomal–dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product, huntingtin. Studies in mouse models and human suggest that the mutation is associated with a deleterious gain of function. There is now a wide range of mouse models for HD, providing important insights into processes associated with disease pathogenesis. These models have been complemented by studies in Drosophila and Caenorhabditis elegans that have allowed the identification of possible modifier loci through suppressor screens.

Section snippets

Neuropathology

HD is characterized by a striking specificity of neuronal loss. The most sensitive region is the striatum, with about 57% loss of cross-sectional area from the caudate nucleus and about 65% loss of the putamen in typical postmortem samples (Fig. 1). Within the striatum, the most sensitive cell population are the medium spiny neurons, which show dendritic changes including recurving of dentrites and altered density, shape and size of spines.

There is loss of cortical volume, particularly in cases

Genetics: gain of function with possible loss of function?

The human HD gene is located on the short arm of chromosome 4 (4p16.3) and encodes a protein called huntingtin, which contains more than 3000 residues [2]. Exon 1 of the wild-type gene contains a polymorphic stretch of uninterrupted CAG trinucleotide repeats, which is translated into a series of consecutive glutamine residues (the polyglutamine tract). Asymptomatic individuals have 35 or fewer CAG repeats, but HD is caused by expansions to 36 or more repeats [3]. There is an inverse

Mouse models have provided insights into normal huntingtin function

Wild-type huntingtin is expressed in many different tissues and is found mainly in the cytoplasm. In neurons it is associated with vesicle membranes and microtubules. Huntingtin appears to be associated with clathrin through huntingtin-interacting protein (HIP-1) 21., 22., 23.. Thus, huntingtin might have a role in vesicle transport and synaptic function.

Wild-type huntingtin is necessary for development, as homozygous knockout mice show embryonic lethality 6., 7., 8.. Furthermore, conditional

Mouse models have revealed potential pathogenic mechanisms of the HD mutation

One of the major objectives of researchers studying diseases such as HD is to try to determine the earliest molecular changes associated with the disease. The rationale for this approach is that it reduces the confounding effects of secondary phenomena that might follow the relevant early changes. The lack of brain tissue from presymptomatic patients largely precludes such studies in human. However, several early changes have been identified in mouse HD models.

Mouse models are a powerful resource for testing therapeutic strategies

The availability of a number of different mouse models of HD has provided powerful tools for preclinical testing of therapeutic strategies, because mice have uniform mutations (similar CAG lengths) and genetic backgrounds. Furthermore, compounds can be tested in the animals before onset of disease and data can be accumulated fairly rapidly, given the short lifespan of many of the HD mouse models. Promising results have been reported with minocycline (a tetracycline derivative that inhibits

Simpler model organisms are powerful tools for supressor screens

A powerful approach to identifying pathways involved in HD pathology and possible protective strategies, is to perform suppressor screens (to identify genes that alleviate or modify the disease), for instance by using P-element insertions in Drosophila [66]. A number of groups have made Drosophila models of polyglutamine expansion diseases 66., 67., 68., 69.. These animals show many of the features of the human disease including cell death and aggregate formation. Suppressor screens have

Conclusions

Murine and other animal models have provided valuable insights into the phenomena that are associated with the development of HD, particularly the early changes. An important challenge will be to discern which of these changes directly affect disease development and how different pathways interact. Suppressor screens in model organisms could make important contributions to such questions. For those working on HD, the diversity of animal models represents an important resource, as different

Acknowledgements

The work in my laboratory on HD is funded by Glaxo Wellcome, The Wellcome Trust, MRC, The Hereditary Disease Foundation, The Violet Richards Charity and The Isaac Newton Trust. I apologise to colleagues whose papers were not referenced owing to space limitations.

Glossary

Anticipation
Phenomenon where the age at onset tends to decrease and/or the severity of the disease tends to increase in successive generations in pedigrees.
Bradykinesia
Slowness of voluntary movements and speech.
Caspase
Class of cysteine proteases that are important mediators of apoptosis.
Choreiform movement (chorea)
Involuntary, purposeless motions; for example, flexing and extending fingers, raising and lowering shoulders, grimacing.
Clathrin
Fibrous protein that forms a lattice shell around

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