Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson's disease

Alterations in the activity of tryptophan 2,3-dioxygenase (TDO) cause imbalances in the levels of serotonin and other neuroactive metabolites which can contribute to motor, psychiatric, gastrointestinal, and other dysfunctions often seen in Parkinson's disease (PD). TDO is a key enzyme of tryptophan metabolism at the entry of the kynurenine pathway (KP) which moderates production of neuroactive compounds primarily outside the central nervous system (CNS). Recent data from experimental models indicate that TDO modulation could have beneficial effects on PD symptoms not targeted by traditional dopamine substitution therapies.Areas covered: Based on data available in PubMed and ClinicalTrials databases up until 1st August 2021, we summarize current knowledge of KP alterations in relation to PD. We overview effects of TDO inhibition in preclinical models of neurodegeneration and discuss findings of the impact of enzyme inhibition on motor, memory and gastrointestinal dysfunctions and neuronal cell loss.Expert opinion: TDO inhibition potentially alleviates motor and non-motor dysfunctions of PD. However, data suggesting harmful effects of long term TDO inhibition raise concerns. To exploit possibilities of TDO inhibitory treatment, development of further selective TDO inhibitor compounds with good bioavailability features and models adequately replicating PD symptoms of systemic origin should be prioritized

Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the CCDC88C Gene

Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the CCDC88C gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense CCDC88C mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the CCDC88C gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described CCDC88C mutations, we carried out in vitro functional tests. The CCDC88C alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the CCDC88C gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the CCDC88C mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that CCDC88C mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes

Immunomodulatory Effects of Genetic Alterations Affecting the Kynurenine Pathway

Several enzymes and metabolites of the kynurenine pathway (KP) have immunomodulatory effects. Modulation of the activities and levels of these molecules might be of particular importance under disease conditions when the amelioration of overreacting immune responses is desired. Results obtained by the use of animal and tissue culture models indicate that by eliminating or decreasing activities of key enzymes of the KP, a beneficial shift in disease outcome can be attained. This review summarizes experimental data of models in which IDO, TDO, or KMO activity modulation was achieved by interventions affecting enzyme production at a genomic level. Elimination of IDO activity was found to improve the outcome of sepsis, certain viral infections, chronic inflammation linked to diabetes, obesity, aorta aneurysm formation, and in anti-tumoral processes. Similarly, lack of TDO activity was advantageous in the case of anti-tumoral immunity, while KMO inhibition was found to be beneficial against microorganisms and in the combat against tumors, as well. On the other hand, the complex interplay among KP metabolites and immune function in some cases requires an increase in a particular enzyme activity for the desired immune response modulation, as was shown by the exacerbation of liver fibrosis due to the elimination of IDO activity and the detrimental effects of TDO inhibition in a mouse model of autoimmune gastritis. The relevance of these studies concerning possible human applications are discussed and highlighted. Finally, a brief overview is presented on naturally occurring genetic variants affecting immune functions via modulation of KP enzyme activity

Progress in the development of kynurenine and quinoline-3-carboxamide derived drugs

The diverse neuro- and immunomodulatory effects of kynurenine pathway (KP) enzymes and metabolites exert offer possibilities for intervention in diseases such as autoimmunity, neurodegeneration and neoplastic processes.This review focuses on data obtained from to the preclinical and clinical use of a KP metabolite analogue and structurally related compounds. 4-Cl-KYN has completed clinical trials in depression without success. However, the good safety data give hope for further trials in suicide prevention, neuropathic pain and dyskinesia. Quinoline-3-carboxiamide derivatives laquinimod, paquinimod and tasquinimod show structural similarities to kynurenines. Laquinimod and paquinimod show promising results in the treatment of autoimmune diseases, tasquinimod is considered primarily as an anti-cancer drug. Data available until 31th of May, 2020 at Clinicaltrials.gov and PubMed have been reviewed.The failure of 4-Cl-KYN for use as an anti-depressant may be related to inadequate concentration, or that the ketamine-like rapid anti-depressant effect is not produced via NMDAR modulation. Further clarification may emerge from studies involving higher drug concentration, and/or from identification of ketamine targets. Clinical application trials in very diverse indications of structurally related quinoline-3-carboxamides and the wide range of their mode of action warrant further studies permitting direct comparison of effects and better target identification

Genetic alterations affecting the genes encoding the enzymes of the kynurenine pathway and their association with human diseases

Tryptophan is metabolized primarily via the kynurenine pathway (KP), which involves several enzymes, including indoleamine 2,3-dioxygenase, tryptophan 2,3 dioxygenase (TDO), kynurenine aminotransferases (KATs), kynurenine monooxygenase (KMO) etc. The majority of metabolites are neuroactive: some of them, such as kynurenic acid, show neuroprotective effects, while others contribute to free radical production, leading to neurodegeneration. Imbalance of the pathway is assumed to contribute to the development of several neurodegenerative diseases, psychiatric disorders, migraine and multiple sclerosis. Our aim was to summarize published data on genetic alterations of enzymes involved in the KP leading to disturbances of the pathway that can be related to different diseases. To achieve this, a PubMed literature search was performed for publications on genetic alterations of the KP enzymes upto April 2017. Several genetic alterations of the KP have been identified and have been proposed to be associated with diseases. Here we must emphasize that despite the large number of recognized genetic alterations, the number of firmly established causal relations with specific diseases is still small. The realization of this by those interested in the field is very important and finding such connections should be a major focus of related research. Polymorphisms of the genes encoding the enzymes of the KP have been associated with autism, multiple sclerosis and schizophrenia, and were shown to affect the immune response of patients with bacterial meningitis, just to mention a few. To our knowledge, this is the first comprehensive review of the genetic alterations of the KP enzymes. We believe that the identification of genetic alterations underlying diseases has great value regarding both treatment and diagnostics in precision medicine, as this work can promote the understanding of pathological mechanisms, and might facilitate medicinal chemistry approaches to substitute missing components or correct the disturbed metabolite balance of KP. © 2018 Elsevier B.V