Dysfunctional kynurenine pathway metabolism in the R6/2 mouse model of Huntington's disease.
Elevated concentrations of neurotoxic metabolites of the kynurenine pathway (KP) of tryptophan degradation may play a causative role in Huntington's disease (HD). The brain levels of one of these compounds, 3-hydroxykynurenine (3-HK), are increased in both HD and several mouse models of the disease. In the present study, we examined this impairment in greater detail using the R6/2 mouse, a well-established animal model of HD. Initially, mutant and age-matched wild-type mice received an intrastriatal injection of (3)H-tryptophan to assess the acute, local de novo production of kynurenine, the immediate bioprecursor of 3-HK, in vivo. No effect of genotype was observed between 4 and 12 weeks of age. In contrast, intrastriatally applied (3)H-kynurenine resulted in significantly increased neosynthesis of (3)H-3-HK, but not other tritiated KP metabolites, in the R6/2 striatum. Subsequent ex vivo studies in striatal, cortical and cerebellar tissue revealed substantial increases in the activity of the biosynthetic enzyme of 3-HK, kynurenine 3-monooxygenase and significant reductions in the activity of its degradative enzyme, kynureninase, in HD mice starting at 4 weeks of age. Decreased kynureninase activity was most evident in the cortex and preceded the increase in kynurenine 3-monooxygenase activity. The activity of other KP enzymes showed no consistent brain abnormalities in the mutant mice. These findings suggest that impairments in its immediate metabolic enzymes jointly account for the abnormally high brain levels of 3-HK in the R6/2 model of HD.
Sathyasaikumar
Korrapati V
KV
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Stachowski
Erin K
EK
Amori
Laura
L
Guidetti
Paolo
P
Muchowski
Paul J
PJ
Schwarcz
Robert
R
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism*; D008659:Metabolic Diseases / Q000209:etiology / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D013997:Time Factors; D014316:Tritium / Q000008:administration & dosage / Q000378:metabolism; D014364:Tryptophan / Q000008:administration & dosage / Q000378:metabolism
C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014316:Tritium; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan