Normal Function of Huntingtin

Huntingtin (HTT) is the 3,144–amino acid protein product of the Huntington's Disease gene (HTT), which can be traced back through 800 million years of evolution. It carries a trinucleotide CAG repeat that encodes polyglutamine (polyQ) at an evolutionarily conserved NH2-terminal position in exon 1. This chapter discusses the discoveries that have mapped the evolutionary history of HTT and the CAG repeat and the critical role of the protein in development as well as its activities in the adult brain. During embryogenesis, HTT is critical for gastrulation, neurulation, and neurogenesis. In the adult brain, HTT acts as an antiapoptotic protein and promotes transcription of neuronal genes and vesicle transport. Subversion or exacerbation of HTT brain function by an abnormally expanded polyQ repeat contributes to neuronal vulnerability in HD and suggests that loss of normal HTT function may be implicated in the disease.