Quinolinic acid catabolism is increased in cerebellum of patients with dominantly inherited olivopontocerebellar atrophy

Abstract

We measured the activities of the enzymes responsible for the metabolism of the excitotoxin quinolinic acid, 3-hydroxyanthranilate oxygenase and quinolinic acid phosphoribosyltransferase, in autopsied brain of 11 patients with olivopontocerebellar atrophy. In cerebellar cortex, severe Purkinje cell loss was evident but with relative preservation of granule cells. As compared with the control subjects (n = 14), mean activity of 3-hydroxyanthranilate oxygenase was normal in cerebellar cortex from the patients with olivopontocerebellar atrophy, whereas quinolinic acid phosphoribosyltransferase activity was markedly increased (+92%, p less than 0.02). No significant changes in enzyme activities were found in samples from occipital cortex. Increased quinolinic acid phosphoribosyltransferase activity may represent a mechanism, in the degenerating cerebellum, to protect quinolinic acid-sensitive granule cells in patients with olivopontocerebellar atrophy.

Blood–Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism

“…For example, brain QUIN levels are higher than normal in hepatic encephalopathy (Moroni et al, 1986), and both brain QUIN and KYNA have been reported to increase with age (Moroni et al, 19846, 1988~). Moreover, elevated activity of 3-hydroxyanthranilate oxygenase, the synthetic enzyme for QUIN, has been found in brains of Huntington's disease victims (Schwarcz et al, 19883), and changes in QUIN catabolism occur in temporal lobe epilepsy (Feldblum et al, 1988) and olivopontocerebellar atrophy (Kish et al, 1991). Because the availability of the essential bioprecursors of QUIN and KYNA (Trp, L-KYN, and probably ANA) is affected by a number of factors (i.e., plasma concentrations and competitive blood-brain barrier transport) that are likely to be altered in disease states, the role of the blood-brain bamer must be considered in future studies of kynurenines in neurological and psychiatric diseases.…”

Regulation of NAD biosynthetic enzymes modulates NAD-sensing processes to shape mammalian cell physiology under varying biological cues

“…Due to the neurotoxic nature of the QA substrate, several studies have investigated the possible enzyme's involvement in the pathogenesis of neurodegenerative disorders characterized by a significant accumulation of QA deriving from KP activation. The increase of the enzyme activity in the brain of patients with Huntington disease [146] and with olivopontocerebellar atrophy [147], the increase of the enzyme level in glial cells of rat models of chronic epilepsy [148] and the increase of mRNA expression in the brain of Alzheimer disease mice [149] appear to suggest a neuroprotective function of the enzyme. However, it is evident that QAPRT activity is not sufficient to fulfill the role of QA scavenger.…”

Enzymology of mammalian NAD metabolism in health and disease

“…Anyway, QaPRT in brain is not able to significantly lower the neurotoxic concentration of Qa produced by the immune cells (90). Even though a significant increase of the enzyme activity has been observed in the brain of Huntington disease patients (93), as well as in the cerebellum of patients with olivopontocerebellar atrophy (94), it is likely that the enzyme is not able to efficiently counteract the dangerous Qa raise in these disorders. It cannot be excluded the possibility that efficiency in Qa degradation might be responsible for the pathological accumulation of the molecule; in fact, it has been observed a local deficit of QaPRT activity in epileptic human brain, which might contribute to the establishment or maintenance of the epileptic focus (95).…”