Targeting Kynurenine 3-Monooxygenase (KMO): Implications for Therapy in Huntingtons Disease

Mathuravani      A. Thevandavakkam; Robert      Schwarcz; Paul      J. Muchowski; Flaviano      Giorgini

Abstract

Huntingtons disease (HD) is an adult onset neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein. Recent work has shown that perturbation of kynurenine pathway (KP) metabolism is a hallmark of HD pathology, and that changes in brain levels of KP metabolites may play a causative role in this disease. The KP contains three neuroactive metabolites, the neurotoxins 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), and the neuroprotectant kynurenic acid (KYNA). In model systems in vitro and in vivo, 3-HK and QUIN have been shown to cause neurodegeneration via a combination of excitotoxic mechanisms and oxidative stress. Recent studies with HD patient samples and in HD model systems have supported the idea that a shift away from the synthesis of KYNA and towards the formation of 3-HK and QUIN may trigger the neuropathological features observed in HD. The enzyme kynurenine 3-monooxygenase (KMO) is located at a critical branching point in the KP such that inhibition of this enzyme by either pharmacological or genetic means shifts the flux in the pathway towards the formation of KYNA. This intervention ameliorates disease-relevant phenotypes in HD models. Here we review the work implicating the KP in HD pathology and discuss the potential of KMO as a therapeutic target for this disorder. As several neurodegenerative diseases exhibit alterations in KP metabolism, this concept has broader implications for the treatment of brain diseases.

Keywords: Huntington's disease, 3-hydroxykynurenine, kynurenine 3-monooxygenase (KMO), kynurenine pathway, kynurenic acid, microglia, neurodegeneration, quinolinic acid, QUIN, KYNA, chorea, bradykinesia, dystonia, Neuropathology, GABA, HD Pathology, polyQ, HEAT, Elongation factor 3, PR65/A, TOR1), Excitotoxicity, AMPA, axon-sparing, tryptophan, serotonin/melatonin, Alzheimer's disease, Parkinson's disease, cerebral malaria, amyotrophic lateral sclerosis, multiple sclerosis, neuronal asphyxia, schizophrenia, TDO, INDOL1, HD neostriatum, locomotor, Saccharomyces cerevisiae, Drosophila, CCL5, RANTES