Dissecting the structural basis of Huntingtin pathogenesis: one molecule at the time

Abstract

Huntington's disease (HD) arises from mutations in the Huntingtin protein (Htt) that expand its polyglutamine (polyQ) repeat beyond a threshold of 35 glutamines. This expansion which occurs in the exon 1 of Htt (Htt-Ex1) leads to aggregation, neuronal death, and HD. Htt-Ex1 consists of 3 parts: i) 17-amino acid N-terminal domain (N17), ii) polyQ tract, and iii) proline-rich domain (PRD). Evidence for HD and other neurodegenerative diseases suggest that aggregates may be inert/protective, while monomeric/oligomeric conformations are the toxic species.