Dysfunction of brain kynurenic acid metabolism in Huntington's disease: focus on kynurenine aminotransferases.
The levels of the neuroprotective excitatory amino acid receptor antagonist kynurenic acid (KYNA) have been previously shown to be reduced in 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 enzymes (kynurenine aminotransferases (KAT) I and II) in 12 regions of brains from late-stage HD patients and control donors (n = 17 each). KYNA levels were measured in the original tissue homogenate. Using [3H]kynurenine as the substrate, enzyme activities were determined in dialyzed 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, when expressed per mg original weight, showed significant decreases (48-55%) in the HD putamen (p < 0.01). Trends toward lower enzyme activities and KYNA concentrations were detected in other brain areas as well. Kinetic analyses, performed in putamen and cerebellum, showed an approximately 3-fold increase in Km values for both KAT I and KAT II in the putamen only. Vmax 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) endogenous KAT activator(s).(ABSTRACT TRUNCATED AT 250 WORDS)
Jauch
D
D
Maryland Psychiatric Research Center, University of Maryland, School of Medicine, Baltimore 21228, USA.
Urbańska
E M
EM
Guidetti
P
P
Bird
E D
ED
Vonsattel
J P
JP
Whetsell
W O
WO
Schwarcz
R
R
D000368:Aged; D001921:Brain / Q000201:enzymology / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007700:Kinetics; D007736:Kynurenic Acid / Q000378:metabolism*; D008190:Lyases; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D008190:Lyases; D007736:Kynurenic Acid