Trends in Genetics
ReviewLessons from animal models of Huntington's disease
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
References (71)
Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioural and morphological changes in heterozygotes
Cell
(1995)Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice
Cell
(1996)A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration
Neuron
(1999)Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease
Cell
(2000)Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse
Cell
(1997)HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and AP2
J. Biol. Chem.
(2001)Huntingtin's neuroprotective activity occurs via inhibition of procaspase-9 processing
J. Biol. Chem.
(2001)Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo
Am. J. Hum. Genet.
(2001)Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation
Cell
(1997)Intranuclear neuronal inclusions in Huntington's disease and dentatorubral pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length
Neurobiol. Dis.
(1998)
Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions
Cell
Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice
Neuron
Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice
Cell
Glutamine repeats and neurodegenerative diseases: molecular aspects
Trends Biochem. Sci.
Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells
J. Biol. Chem.
Mutant huntingtin enhances excitotoxic cell death
Mol. Cell. Neurosci.
Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex
Neurosci. Lett.
Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production
Exp. Neurol.
Mice transgenic for the human Huntington's disease mutation have reduced sensitivity to kainic acid toxicity
Brain Res. Bull.
Huntington disease
J. Neuropathol. Exp. Neurol.
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
Cell
Phenotypic characterisation of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats
Am. J. Hum. Genet.
The molecular biology of Huntington's disease
Psychol. Med.
Inactivation of the mouse Huntington's disease gene homolog Hdh
Science
Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homolog
Nat. Genet.
Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion
Nat. Genet.
Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin
Hum. Mol. Genet.
Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD Cdna
Nat. Genet.
Changes in cortical and striatal neurons predict behavioural and electrophysiological abnormalities in a transgenic murine model of Huntington's disease
J. Neurosci.
A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice
Hum. Mol. Genet.
Enhanced sensitivity to N-methyl-d-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease
J. Neurosci. Res.
Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease gene
J. Neurosci. Res.
Neurological abnormalities in a knock-in mouse model of Huntington's disease
Hum. Mol. Genet.
Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease
Science
The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis
Hum. Mol. Genet.
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