An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation

Abstract

Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

Suicide and Lyme and associated diseases

“…Quinolinic acid correlates significantly with guilt, and the ratio of quinolinic acid/3-hydroxykynurenine correlates significantly with guilt and psychomotor agitation 91. Quinolinic acid levels also correlate with increased suicidal risk 92. High cerebrospinal fluid quinolinic acid levels correlate with high suicidal intent 93.…”

A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson’s Disease

“…In fact, alterations in the levels of the kynurenine pathway metabolites have been implicated in several neurodegenerative diseases, including Alzheimer's, and PD and modulation of neuroactive kynurenine metabolites has been proposed as desirable for neuroprotection [9]. ACMSD, expressed in liver, kidney and brain, has previously been related to neuropsychiatric disorders because of its crucial position in the metabolism of tryptophan degradation [17,18].…”

Positive association between Toxoplasma gondii IgG serointensity and current dysphoria/hopelessness scores in the Old Order Amish: a preliminary study

“…However, Engin et al [63] reported that during infection with T. gondii , breakdown of tryptophan may be induced via other unknown pathways as well, which may involve interactions between TDO, IDO and nitric oxide (NO), with NO possibly inhibiting complete exhaustion of tryptophan in acute infection with T. gondii . Studies, including ours, in participants with depressive disorders, have previously linked increased plasma levels of kynurenine [64] and its metabolite quinolinic acid [65, 66] to a history of suicide attempts [67]. …”