Huntington disease: advances in molecular and cell biology.

Huntington disease is an inherited neurodegeneration, for which the associated mutation was isolated in 1993. The mutation is an expansion of a CAG trinucleotide repeat, which translates to give a polyglutamine tract at the N-terminus of a large protein, huntingtin. Neither the normal nor the pathogenic functions of this protein have been identified, but it is clear that pathogenesis is mediated through the expanded polyglutamine tract within the protein, and that polyglutamine is toxic to cells. A number of proteins which interact with the N-terminal region of huntingtin have been isolated, but this has not, so far, yielded a rationale for pathogenesis. Huntingtin is found in areas of the brain that degenerate in this disease but is also associated with pathogenic inclusions in Alzheimer disease and Pick disease. It is possible that Huntington disease has pathogenic mechanisms in common with these other neurodegenerative diseases, and that the mechanism may relate to the formation of abnormal, cytoskeletal-associated, inclusions within cells.