title: 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.
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Brundin
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Sellgren
authors.affiliation: Faculty of Medicine and Health Sciences Macquarie University, Sydney, NSW, Australia.
authors.forename: C K
authors.initials: CK
authors.lastname: Lim
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Grit
authors.affiliation: Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Pålsson
authors.affiliation: Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Landén
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Samuelsson
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Lundgren
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Brundin
authors.affiliation: Division of Biological Chemistry, Innsbruck Medical University, Center for Chemistry and Biomedicine, Innsbruck, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.|Rocky Mountain MIRECC, Denver, CO, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Postolache
authors.affiliation: Section for Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Traskman-Bendz
authors.affiliation: Faculty of Medicine and Health Sciences Macquarie University, Sydney, NSW, Australia.|NHMRC Centre of Research Excellence in Suicide Prevention (CRESP), Randwick, NSW, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Guillemin
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Erhardt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002262:Carboxy-Lyases / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006801:Humans; D007249:Inflammation; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010848:Picolinic Acids / Q000097:blood / Q000134:cerebrospinal fluid*; D020641:Polymorphism, Single Nucleotide; D017378:Quinolinic Acid / Q000097:blood / Q000134:cerebrospinal fluid*; D016728:Self-Injurious Behavior / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics*; D059020:Suicidal Ideation; D013406:Suicide, Attempted; D055815:Young Adult
chemical_list: D010848:Picolinic Acids; D007737:Kynurenine; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase; D017378:Quinolinic Acid; C030614:picolinic acid