Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington's disease.
The neurodegenerative disease Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the protein huntingtin (htt). Although the gene encoding htt was identified and cloned more than 15 years ago, and in spite of impressive efforts to unravel the mechanism(s) by which mutant htt induces nerve cell death, these studies have so far not led to a good understanding of pathophysiology or an effective therapy. Set against a historical background, we review data supporting the idea that metabolites of the kynurenine pathway (KP) of tryptophan degradation provide a critical link between mutant htt and the pathophysiology of HD. New studies in HD brain and genetic model organisms suggest that the disease may in fact be causally related to early abnormalities in KP metabolism, favoring the formation of two neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, over the related neuroprotective agent kynurenic acid. These findings not only link the excitotoxic hypothesis of HD pathology to an impairment of the KP but also define new drug targets and therefore have direct therapeutic implications. Thus, pharmacological normalization of the imbalance in brain KP metabolism may provide clinical benefits, which could be especially effective in early stages of the disease.
Schwarcz
Robert
R
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA. rschwarc@mprc.umaryland.edu
Guidetti
Paolo
P
Sathyasaikumar
Korrapati V
KV
Muchowski
Paul J
PJ
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000139:chemically induced* / Q000235:genetics*; D007737:Kynurenine / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D014364:Tryptophan / Q000378:metabolism
D010455:Peptides; D017470:Receptors, Glutamate; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C097188:polyglutamine; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid; D004298:Dopamine