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Targeting Kynurenine 3-Monooxygenase (KMO): Implications for Therapy in Huntington's Disease

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Huntington's 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.

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

Document Type: Research Article

Publication date: 2010-12-01

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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