Huntington's disease: seeing the pathogenic process through a genetic lens

Trends Biochem Sci. 2006 Sep;31(9):533-40. doi: 10.1016/j.tibs.2006.06.009. Epub 2006 Jul 10.


Thirteen years ago, the culmination of genetic rather than biochemical strategies resulted in the identification of the root cause of Huntington's disease: an expanded CAG trinucleotide repeat that leads to an elongated polyglutamine tract in the huntingtin protein. Since then, biochemical and cell biological attempts to elucidate pathogenesis have largely focused on N-terminal polyglutamine-containing huntingtin fragments. However, continued application of genetic strategies has suggested that the disease process is, in fact, triggered by the presence of expanded polyglutamine in intact huntingtin. An increased emphasis on the earliest presymptomatic stages of the disease, facilitated by incorporating genetic lessons from human patients into the search for biochemical targets, could provide a route to a rational treatment to prevent or slow the onset of this devastating neurodegenerative disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Heredodegenerative Disorders, Nervous System / genetics
  • Heredodegenerative Disorders, Nervous System / pathology
  • Heredodegenerative Disorders, Nervous System / prevention & control
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / pathology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peptides / metabolism


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • polyglutamine