DYSFUNCTION OF BRAIN KYNURENIC ACID METABOLISM IN HUNTINGTONS-DISEASE- FOCUS ON KYNURENINE AMINOTRANSFERASES

The levels of the neuroprotective excitatory amino acid receptor antag onist kynurenic acid (KYNA) have been previously shown to be reduced i n several regions of the brain of Huntington's disease (HD) patients. Thus, KYNA has been speculatively linked to the pathogenesis of HD. We have examined KYNA levels and the activity of its two biosynthetic en zymes (kynurenine aminotransferases (KAT) I and II) in 12 regions of b rains from late-stage HD patients and control donors (n = 17 each). KY NA levels were measured in the original tissue homogenate. Using [H-3] kynurenine as the substrate, enzyme activities were determined in dial yzed tissue homogenates. KYNA levels in the caudate nucleus decreased from 733 +/- 95 in controls to 401 +/- 62 fmol/mg tissue in HD (p < 0. 01). The activity of both enzymes was highest in cortical areas (e.g. control frontal cortex: KAT I: 148 +/- 18 fmol/mg tissue/h; KAT II: 25 +/- 2 fmol/mg tissue/h). The activities of both KAT I and KAT II, whe n expressed per mg original weight, showed significant decreases (48-5 5%) in the HD putamen (p < 0.01). Trends toward lower enzyme activitie s and KYNA concentrations were detected in other brain areas as well. Kinetic analyses, performed in putamen and cerebellum, showed an appro ximately 3-fold increase in K-m values for both KAT I and KAT II in th e putamen only. V-max values remained unchanged in the HD brain. These findings indicate a selective impairment in KYNA biosynthesis in the neostriatum of HD patients, possibly due to the loss of (an) endogenou s KAT activator(s). Future studies should examine whether the demonstr ated dysfunction in the production of the endogenous neuroprotecive ag ent KYNA is causally related to the neurodegenerative process in HD.