Trinucleotide-repeat expansions and neurodegenerative disease: a mechanism of pathogenesis

1. Studies of a number of hereditary neurodegenerative diseases, the most common of which is Huntington's disease, have identified the expansion of trinucleotide repeats as a common causative mutation. 2. The diseases are caused by expansions of CAG repeats, encoding polyglutamine tracts, within the coding regions of a variety of unrelated genes. The mechanism whereby this specific genetic instability leads to selective neurodegeneration is currently unknown. 3. Our current understanding of these polyglutamine expansion neurodegenerative diseases is outlined. A potential mechanism is discussed whereby subtle alterations in glutamine, and consequently glutamate levels, may induce chronic excitotoxicity and slow cell death in neuronal populations possessing specific glutamate receptors. The potential role of glutamate receptor-mediated changes to intracellular calcium levels and energy metabolism in the neurodegenerative pathway is also addressed.