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Experimental therapeutics: preclinical
B06 Validation of KMO as a candidate therapeutic target for Huntington's disease in Drosophila melanogaster
  1. S Campesan1,
  2. E W Green1,
  3. K V Sathyasaikumar2,
  4. C Breda1,
  5. P J Muchowski3,4,5,
  6. R Schwarcz2,
  7. C P Kyriacou1,
  8. F Giorgini1
  1. 1Department of Genetics, University of Leicester, Leicester, UK
  2. 2Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
  3. 3Gladstone Institute of Neurological Disease, Department of Biochemistry, University of California, San Francisco, California, USA
  4. 4Gladstone Institute of Neurological Disease, Department of Biophysics, University of California, San Francisco, California, USA
  5. 5Gladstone Institute of Neurological Disease, Department of Neurology, University of California, San Francisco, California, USA

Abstract

Metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of Huntington's disease (HD). Our previous studies have shown that genetic and pharmacological inhibition of the KP enzyme kynurenine-3 monooxygenase (KMO) reduces toxicity of a mutant huntingtin (htt) fragment in yeast, likely by reduction of neurotoxic KP metabolites. Here we test whether a loss of function allele (cn3) of the Drosophila homologue of KMO (cinnabar, cn) rescues HD relevant phenotypes in flies expressing a huntingtin (Htt) exon 1 93Q fragment (Htt93Q) via the UAS/GAL4 system (driven pan-neuronally by the elav promoter). To this end, we analysed neurodegeneration via rhabdomere number in the eye, locomotor activity as well as eclosion (emergence of the adult fly from its pupal case) and lifespan. In addition, levels of the KP metabolites 3-hydoxykynurenine (3-HK) and kynurenic acid (KYNA) were determined by HPLC in adult flies. Neurodegeneration in Htt93Q expressing flies was accompanied by a significant 1.9-fold increase in the ratio between the neurotoxic metabolite 3-HK and the neuroprotective metabolite KYNA. Genetic impairment of the Drosophila KMO homologue dramatically increased the number of rhabdomeres per ommatidium in Htt93Q expressing flies compared with flies expressing Htt93Q alone. Moreover, cn3 flies expressing Htt93Q showed a significant 2.2-fold increase in KYNA and a significant increase in total locomotor activity, eclosion percentage and lifespan compared to controls. Taken together, these data demonstrate that genetic inhibition of KMO ameliorates HD relevant phenotypes and thereby support the hypothesis that increased flux through the central KP contributes to neurotoxicity in HD models. More generally, our results support the idea of KMO as a candidate therapeutic target for HD, and that shifting KP metabolism towards the production of KYNA may be neuroprotective in patients.

  • KMO
  • Drosophila
  • kynurenine

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