MOLECULAR ASPECTS OF HUNTINGTONS-DISEASE

Huntington's disease (HD) is a progressive neurodegenerative disease s triking principally medium spiny GABAergic neurons of the caudate nucl eus of the basal ganglia, It affects about one in 10,000 individuals a nd is transmitted in an autosomal dominant fashion. The molecular basi s of the disease is expansion of the trinucleotide CAG in the first ex on of a gene on chromosome four. The CAG repeats are translated to pol yglutamine repeats in the expressed protein, huntingtin, The normal fu nction of huntingtin remains incompletely characterized, but based upo n recently defined protein-protein interactions, it appears to be asso ciated with the cytoskeleton and required for neurogenesis, Huntingtin has been demonstrated to interact with such proteins as HAP1, HIP1, m icrotubules, GADPH, calmodulin, and an ubiquitin-conjugating enzyme. P olyglutamine expansion alters many of these interactions and leads to huntingtin aggregation and the formation of neuronal nuclear inclusion s, ultimately culminating in cell death. In this review we discuss the molecular aspects of HD, including the present understanding of hunti ngtin-protein interactions, studies with transgenic mice, and postulat ed mechanisms of huntingtin aggregation. (C) 1998 Wiley-Liss, Inc.