Early kynurenergic impairment in Huntington's disease and in a transgenic animal model.
Several neuroactive metabolites of the kynurenine pathway of tryptophan degradation have been speculatively linked to the pathophysiology of Huntington's Disease (HD). Here we demonstrate that the levels of two of these metabolites, the free radical generator 3-hydroxykynurenine (3HK) and the neuroprotectant kynurenate (KYNA), are increased in the neostriatum of stage 1 HD patients and in the brain of mice transgenic for full-length mutant huntingtin. In both cases, the elevation in 3HK was far more pronounced, resulting in significant increases in the 3HK/KYNA ratios. These data suggest that abnormal kynurenine pathway metabolism may play a role during the early phases of the neurodegenerative process in HD.
Guidetti
P
P
Maryland Psychiatric Research Center, Baltimore, MD 21228, USA.
Reddy
P H
PH
Tagle
D A
DA
Schwarcz
R
R
D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D007737:Kynurenine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019579:Neocortex / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009687:Nuclear Proteins; C005045:3-hydroxykynurenine; D007737:Kynurenine