Modelling Huntington’s disease

Abstract

Huntington’s disease (HD) is one of a group of inherited neurodegenerative disorders caused by a polyglutamine (CAG)-repeat expansion. The pathology of these disorders is associated with the presence of neuronal intranuclear inclusions, which contain the polyglutamine- repeat-containing protein that is specific to the disease, along with ubiquitin. Sathasivam et al.1xFormation of polyglutamine inclusions in non-CNS tissue. Sathasivam, K. et al. Hum. Mol. Genet. 1999; 8: 813–822Crossref | PubMedSee all References1 report the formation of nuclear inclusions (NIs) in non-neuronal tissue in previously described transgenic mice that express exon 1 of the human HD gene that contains a highly expanded CAG repeat. In this model, NIs were found in several tissues, including cardiac and skeletal muscle, liver, kidney, adrenal gland and pancreas. They report a correlation between the presence of NIs and a progressive decrease in organ size. It is not known whether similar non-neuronal NIs occur in human HD patients, and as such the relevance of this aspect of the model is unclear. Despite this, the presence of NIs in tissues such as skeletal muscle provides a good system to study NIs and to investigate ways to prevent their formation.Although the association of NIs with HD is well documented, their role in the pathology of the disease remains unproven, and an unknown property of the expanded polyglutamine repeat that is independent of NI formation might underlie certain aspects of the disease. A new mouse model, described by Shelbourne et al.2xA Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Shelbourne, P.F. et al. Hum. Mol. Genet. 1999; 8: 763–774Crossref | PubMedSee all References2, provides a valuable tool to study this possibility. This mouse has a stretch of 72–80 CAG repeats inserted into the endogenous Hdh gene. This ‘knockin’ mutation is similar to the human HD mutation as the mice express full-length mutant huntingtin in a wild-type genomic context. From a genetic viewpoint, this model appears to closely mirror the human HD mutation. As in humans, the expanded CAG repeat is unstable and a parent-of-origin effect on the repeat length is observed, with expansions tending to be associated with paternal transmission and contractions being associated with maternal transmission. The brains of the mutant mice are histologically normal with no evidence of NI formation. However, a reduction in brain size is seen in the mutant strains. The mutant mice also displayed chronic aggressive behaviour; human HD patients often exhibit symptoms such as irritability and aggression and ∼50% of patients present with psychiatric symptoms. These mice might therefore provide a model for the psychiatric disorder in HD.The knockin model was used to study the possible basis of cognitive impairment in HD (Ref. 3xImpaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Usdin, M.T. et al. Hum. Mol. Genet. 1999; 8: 839–846Crossref | PubMedSee all ReferencesRef. 3). Long-term potentiation (LTP) is the sustained increase in synaptic strength following a high-frequency conditioning stimulus. LTP provides a model for a mechanism that underlies some forms of learning and memory. LTP was significantly reduced in the stratum radiatum of area CA1 of hippocampal slices from the mutant mice. Post-tetanic potentiation and paired-pulse facilitation were also shown to be impaired, suggesting that the presynaptic terminals might be less able to sustain neurotransmitter release with repetitive stimulation. This was tested by monitoring the opening of N-methyl-d-aspartate (NMDA) channels by glutamate release. Glutamatergic synapses in area CA1 were shown to transmit normally in response to single stimuli but were impaired in their ability to release neurotransmitter at moderate levels of stimulation. The authors propose that the polyglutamine expansion might interfere with neurotransmitter release at the presynaptic terminals. This hypothesis is consistent with previous reports of wild-type HD protein being associated with microtubules and synaptic vesicles.This new mouse model provides evidence that some of the symptoms of HD might be independent of NI formation and might precede neurodegeneration. The two mouse models provide insights into distinct aspects of HD; taken together they should complement each other to facilitate research into the molecular basis and treatment of this disease.