Molecular aspects of Huntington's disease

Huntington's disease (HD) is a progressive neurodegenerative disease striking principally medium spiny GABAergic neurons of the caudate nucleus of the basal ganglia, It affects about one in 10,000 individuals and is transmitted in an autosomal dominant fashion. The molecular basis of the disease is expansion of the trinucleotide CAG in the first exon of a gene on chromosome four. The CAG repeats are translated to polyglutamine repeats in the expressed protein, huntingtin, The normal function of huntingtin remains incompletely characterized, but based upon recently defined protein-protein interactions, it appears to be associated with the cytoskeleton and required for neurogenesis, Huntingtin has been demonstrated to interact with such proteins as HAP1, HIP1, microtubules, GADPH, calmodulin, and an ubiquitin-conjugating enzyme. Polyglutamine expansion alters many of these interactions and leads to huntingtin aggregation and the formation of neuronal nuclear inclusions, ultimately culminating in cell death. In this review we discuss the molecular aspects of HD, including the present understanding of huntingtin-protein interactions, studies with transgenic mice, and postulated mechanisms of huntingtin aggregation. (C) 1998 Wiley-Liss, Inc.