The molecular biology of Huntington's disease

Background. Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive de mentia, psychiatric symptoms and an incapacitating choreiform movement diso rder, culminating in premature death. HD is caused by an increased CAG repe at number in a gene coding for a protein with unknown function, called hunt ingtin. The trinucleotide CAG codes for the amino acid glutamine and the ex panded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract). Methods. This review describes the epidemiology, clinical symptomatology, n europathological features and genetics of HD. The main aim is to examine im portant findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases ca used by expanded polyglutamine tracts. Results. Selective death of striatal and cortical neurons occurs. It is lik ely that the HD mutation confers a deleterious gain of function on the prot ein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin d evelop in patients and transgenic mouse models of HD. Other proposed mechan isms contributing to neuropathology include excitotoxicity, oxidative stres s, impaired energy metabolism, abnormal protein interactions and apoptosis. Conclusions. Although many interesting findings have accumulated from studi es of HD and other polyglutamine diseases, there remain many unresolved iss ues pertaining to the exact roles of intranuclear inclusions and protein ag gregates, the mechanisms of selective neuronal death and delayed onset of i llness. Further knowledge in these areas will inspire the development of no vel therapeutic strategies.