Background. Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal
dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an
incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an
increased CAG repeat number in a gene coding for a protein with unknown function, called
huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG
repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract).
Methods. This review describes the epidemiology, clinical symptomatology, neuropathological
features and genetics of HD. The main aim is to examine important findings from animal and
cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD
and other diseases caused by expanded polyglutamine tracts.
Results. Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation
confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing
huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed
mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired
energy metabolism, abnormal protein interactions and apoptosis.
Conclusions. Although many interesting findings have accumulated from studies of HD and other
polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of
intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and
delayed onset of illness. Further knowledge in these areas will inspire the development of novel