Molecular Pathogenesis of Huntington’s Disease

Huntington’s disease (HD) is a genetic neurodegenerative disease with a complex set of symptoms and an insidious progression that continues until death. The cause of HD is the pathological expansion of an unstable (CAGn) trinucleotide repeat within the coding region of the HD gene (for references, see 1). The CAG repeat codes for a polyglutamine repeat in the huntingtin (htt) protein. To date, 9 other ‘polyglutamine repeat’ diseases have been identified, including spinobulbar muscular atrophy (SBMA), several of the spinocerebellar ataxias (SCA1,2,3,6,7 and 17) and dentatorubralpallidoluysian atrophy (DRPLA). In each of these diseases, the protein carrying the mutation and also the distribution of neuronal loss is different. (The different protein context in each disease is likely to be responsible for the difference in the patterns of neurodegeneration). However, the fact that all of these diseases are caused by a similar mutation, coupled with the fact that they are all are dominant, (except SBMA that is X-linked), adult-onset, progressive neurodegenerative diseases, suggests that they may have a common underlying pathological mechanism.