Huntington's disease: seeing the pathogenic process through a genetic lens.
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.
Gusella
James F
JF
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, 185 Cambridge Street, Boston, MA 02114, USA. gusella@helix.mgh.harvard.edu
MacDonald
Marcy E
ME
D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine