Quinolinic acid phosphoribosyltransferase in human and rat brain: activity in Huntington's disease and in quinolinate-lesioned rat striatum.
Quinolinic acid (QUIN) is an excitotoxic compound which is present in rat and human brain and has been hypothetically linked to neurodegenerative disorders including Huntington's disease (HD). We have examined the biochemistry of QUIN by measuring the activity of its degradative enzyme QUIN phosphoribosyltransferase (QPRT) in post-mortem samples of human brain from normal and HD subjects, and in the striata of rats injected intrastriatally with QUIN. In normal human brain, QPRT activity was highest in the caudate nucleus and substantia nigra, less in the thalamus, hypothalamus, frontal cortex and hippocampus and lowest in the spinal cord and cerebellum. QPRT activity in HD caudate tended to be higher than control, the respective values (mean +/- S.E.M., n = 9 for each group) being 365.7 +/- 52.5 and 242.0 +/- 50.8 fmol/h/mg protein (0.1 greater than P greater than 0.05, t-test); values of enzyme activity in the putamen were similar between normal and HD groups. Kinetic analyses indicated that the Km values for QUIN and its co-substrate phosphoribosylpyrophosphate (PRPP) were similar in normal and HD caudate, but Vmax values were elevated in HD caudate. Rat striatal QPRT activity was increased in QUIN-injected striata, and when expressed as a percentage of the contralateral side it was 163.6% at 2 days, 344.4% at 14 days and 198.8% at 7 months post-injection. Kinetic analyses in the 7-month QUIN-injected group showed an increase of Vmax but no change of Km values for QUIN or PRPP. The results indicate that QPRT activity increases in response to specific neurodegenerative events.(ABSTRACT TRUNCATED AT 250 WORDS)
Foster
A C
AC
Whetsell
W O
WO
Bird
E D
ED
Schwarcz
R
R
D000368:Aged; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002421:Caudate Nucleus / Q000201:enzymology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010430:Pentosyltransferases / Q000378:metabolism*; D011699:Putamen / Q000201:enzymology; D011725:Pyridines / Q000494:pharmacology*; D011805:Quinolinic Acids / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating)
D011725:Pyridines; D011805:Quinolinic Acids; D002795:Choline O-Acetyltransferase; D010430:Pentosyltransferases; D000098553:Nicotinate-Nucleotide Diphosphorylase (Carboxylating); D005968:Glutamate Decarboxylase