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Crossroads of Kynurenine Pathway Offers Leads for Schizophrenia and Neurodegenerative Disease Alike

12 August 2011. A key enzyme in the kynurenine pathway, which appears to have a pivotal role in normal brain function, may offer traction against very different brain disorders, according to two recent studies. Inhibiting the enzyme kynurenine 3-monooxygenase (KMO) prevents synapse loss and ameliorates symptoms in mouse models of Alzheimer's and Huntington's diseases, according to a study published in Cell on June 10. Another study in the July issue of Archives of General Psychiatry finds that KMO levels are lower in postmortem brain tissue from individuals with schizophrenia relative to controls. Together, the results suggest that manipulations of the kynurenine pathway might help rectify neurodegenerative and psychiatric diseases alike.

Though a classic biochemical pathway identified in the 1960s, it was not clear the kynurenine pathway had anything to do with the brain until some 20 years later, when researchers found that the same pathway existed in the brain, and that some of its products modulated neurotransmitter systems. The pathway is responsible for degrading tryptophan, by first converting it into kynurenine, which then feeds into two branches of the pathway. One branch operates in microglial cells and ultimately turns kynurenine into nicotinamide adenine dinucleotide (NAD+), making neurotoxic byproducts 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) along the way. The other branch resides in astrocytes and converts kynurenine into kynurenic acid (KYNA), which is considered neuroprotective because of its ability to inhibit N-methyl D-aspartate receptors (NMDARs) and a subtype of nicotinic acetylcholine receptors (nAChRs). Evidence suggests that an overly active "neurotoxic" branch of the pathway participates in the neuronal demise marking neurodegenerative diseases like Huntington's (Schwarcz et al., 2010), whereas excessive production of KYNA by the "neuroprotective" branch contributes to schizophrenia (Wonodi et al., 2010).

"The neuroactive kynurenines are brain chemicals that, though made in astrocytes and microglial cells, are like neurotransmitters in that too much of them or too little of them is bad," Robert Schwarcz of the Maryland Psychiatric Research Center in Baltimore, who was involved in both studies, told SRF.

Activity in KMO, the enzyme that converts kynurenine into 3-HK, may regulate the relative balance between the two branches. Inhibiting KMO activity could divert kynurenine into the "neuroprotective" branch, resulting in elevated KYNA levels that could then help stem the neuron loss in neurodegenerative diseases. In the Cell paper, Paul Muchowski of the University of California, San Francisco, Schwarcz, and colleagues found that such an inhibitor, called JM6, worked in this way, elevating KYNA in the brain and preventing synaptic loss and behavioral deficits in mouse models of Alzheimer's and Huntington's (see Alzheimer Research Forum news story).

But getting KMO activity just right may be critical for a particular disorder, as Schwarcz and colleagues found signs of underactive KMO in postmortem brain tissue from individuals with schizophrenia in their study published in the Archives paper. This KMO downregulation provides an explanation for the increased levels of KYNA consistently found in postmortem brain tissue (Schwarcz et al., 2001) and in the cerebrospinal fluid (Nilsson et al., 2005) of individuals with schizophrenia. A KYNA increase, though neuroprotective, could impair signaling through NMDA receptors—something that fits with the glutamate hypothesis of schizophrenia, which proposes that underactive glutamate signaling in the brain underlies the disorder (see SRF hypothesis). Similarly, KYNA antagonizes a type of nAChR whose function may be compromised in schizophrenia as well (Freedman et al., 1995).

"With kynurenic acid, we have an endogenous compound that blocks receptors which many people believe are involved in certain aspects of schizophrenia," Schwarcz said. "It's really an interesting confluence."

The eye movements have it
To get a handle on KMO status in schizophrenia, first author Ikwunga Wonodi and colleagues compared KMO mRNA and enzymatic activity in postmortem brain samples from the frontal eye field (FEF), a region critical for making different kinds of eye movements, some of which are impaired in schizophrenia. Comparing samples from 32 schizophrenia donors to those from 32 individuals with no psychiatric history, but matched on sex, age, and postmortem interval, revealed a 33 percent decrease in KMO mRNA and a 30 percent decrease in KMO activity in schizophrenia. These results did not depend on medication history.

The researchers then looked at two single nucleotide polymorphisms (SNPs) in the KMO genes from the brain donors, and found that one—previously associated with schizophrenia (see SZGene entry)—trended toward an association with KMO mRNA expression: those homozygous for the major allele (CC) exhibited less KMO mRNA than those carrying the minor allele (CT or TT), though this finding did not quite reach statistical significance.

To try to understand what this KMO variant might mean behaviorally, the researchers turned to individuals with schizophrenia and healthy controls who had been genotyped for this SNP. Of these, 286 performed a predictive pursuit task in which they tracked a moving target with their eyes, even when the target briefly disappeared, and 156 performed a task measuring visuospatial working memory in which they had to, after a delay, move their eyes to the place a target had previously appeared. Combining schizophrenia and control data, the researchers found that the eye movements of those genotyped as CC did not keep up with the pursuit target as well as those carrying the minor TT allele, and they were not as accurate in looking to the location of a previously shown target.

No association was found between the CC genotype and schizophrenia, but divvying up the groups by pursuit capability revealed that the CC genotype may slow eye tracking more profoundly in schizophrenia than in controls. This strategy of looking at how intermediate phenotypes, rather than disease itself, associate with genetic variants may help detect the small effects of genes contributing to schizophrenia (Meyer-Lindenberg et al., 2006). Though how this SNP is related to KMO activity is unclear, the CC genotype might somehow downregulate KMO, as hinted by the postmortem data.

Counteracting KAT II
The results bolster the idea that decreasing KYNA levels may be a way to alleviate schizophrenia symptoms. But rather than boosting KMO activity to achieve this—something that runs the risk of generating too many neurotoxic compounds—researchers are focused on inhibiting the enzyme that synthesizes KYNA from kynurenine in the brain, called kynurenine aminotransferase II (KAT II). Selective KAT II inhibitors have been developed (e.g., Pellicciari et al., 2006), and they can markedly reduce KYNA levels without changing activity in the 3-HK- and QUIN-producing branch of the pathway (Amori et al., 2009). When administered to rats, KAT II inhibitors enhance cognition: intraventricular injections of a KAT II inhibitor in rats can improve their performance in the Morris water maze, a test of working memory and hippocampal function (Pocivavcek et al, 2011). Similarly, a brain-permeable KAT II inhibitor developed by Pfizer has been reported to improve the performance of rats and nonhuman primates in attention and working memory tasks, but it did not affect behaviors related to psychosis (see SRF related news story).

Though future research will have to explore the effects of chronic KAT II inhibition to see whether it might be a safe therapeutic for schizophrenia, the new findings suggest that tweaking the kynurenine pathway may offer an efficient, comprehensive way to alter multiple neurotransmitter systems in concert. Even a familiar biochemistry pathway may hold new treatment ideas for brain disorders.—Michele Solis.

References:
Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, Muchowski PJ. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011 Jun 10; 145:863-74. Abstract

Wonodi I, Stine OC, Sathyasaikumar KV, Roberts RC, Mitchell BD, Hong LE, Kajii Y, Thaker GK, Schwarcz R. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch Gen Psychiatry. 2011 Jul; 68:665-674. Abstract

Comments on Related News


Related News: NYAS 2011—New Molecular Targets for Schizophrenia

Comment by:  Jim Woodgett
Submitted 26 April 2011
Posted 27 April 2011

Several of the reports from the NYAS meeting describe the potential role of GSK-3β in DISC1 functions. This is one of two isoforms, and the other, GSK-3α, tends to get short shrift from researchers. This is problematic for several reasons. Firstly, the two isoforms, despite being derived from distinct genes, are essentially identical within their catalytic domains. Consequently, there are no small molecule inhibitors that that are isoform selective, and the two proteins are highly redundant (albeit not completely) in function. Secondly, in the case of DISC1, there are new data indicating a role for GSK-3α in DISC1 functions. Small molecule (isoform indiscriminate) inhibitors of GSK-3 restore behavioral deficits of DISC1 L100P animals, and this is also achieved by genetic inactivation of one allele of GSK-3α (Lipina et al., 2011). Examination of the brains of the DISC1 and DISC1/GSK-3α+/- animals revealed that dendritic spine density deficits observed in DISC1 L100P brains were restored upon deletion of one copy of GSK-3α (Lee et al., 2011).

From a therapeutic point of view, there appears to be no easy way to selectively inhibit only one isoform of GSK-3 (the only means is via RNA interference), so perhaps it is fortunate that both isoforms appear to play similar roles? Birds, on the other hand, appear to have selectively lost GSK-3α, though the consequences in terms of brain development and function are currently unclear (Alon et al., 2011).

References:

Lipina TV, Kaidanovich-Beilin O, Patel S, Wang M, Clapcote SJ, Liu F, Woodgett JR, Roder JC. (2011). Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse 65(3):234-48. Abstract

Lee FH, Kaidanovich-Beilin O, Roder JC, Woodgett JR, Wong AH. (2011) Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice. Schizophr Res. Abstract

Alon LT, Pietrokovski S, Barkan S, Avrahami L, Kaidanovich-Beilin O, Woodgett JR, Barnea A, Eldar-Finkelman H. (2011) Selective loss of glycogen synthase kinase-3α in birds reveals distinct roles for GSK-3 isozymes in tau phosphorylation. FEBS Lett. 585(8):1158-62. Abstract

View all comments by Jim Woodgett