Transgenic models of Huntington's disease

CAG/polyglutamine expansion has been shown to form the molecular basis of an increasing number of inherited neurodegenerative diseases. The mutation is likely to act by a dominant gain of function but the mechanism by which it leads to neuronal dysfunction and cell death is unknown. The proteins harbouring these polyglutamine tracts are unrelated and without exception are widely expressed with extensively overlapping expression patterns. The factors governing the cell specific nature of the neurodegeneration have yet to be understood. Upon a certain size threshold, expanded CAG repeats become unstable on transmission and a modest degree of somatic mosaicism is apparent. Similarly, the molecular basis of the instability and its tissue specificity has yet to be unravelled. Recent reports describing the first mouse models of CAG/polyglutamine disorders indicate that it will be possible to model both the pathogenic mechanism and the CAG repeat instability in the mouse. This has great potential and promise for uncovering the molecular basis of these diseases and developing therapeutic interventions.