title: The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease.
abstract: Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington's disease (HD) [1]. A central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein [2]. Here we exploit a transgenic Drosophila melanogaster model of HD to interrogate the therapeutic potential of KP manipulation. We observe that genetic and pharmacological inhibition of kynurenine 3-monooxygenase (KMO) increases levels of the neuroprotective metabolite kynurenic acid (KYNA) relative to the neurotoxic metabolite 3-hydroxykynurenine (3-HK) and ameliorates neurodegeneration. We also find that genetic inhibition of tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting step in the pathway, leads to a similar neuroprotective shift toward KYNA synthesis. Importantly, we demonstrate that the feeding of KYNA and 3-HK to HD model flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. This study provides the first genetic evidence that inhibition of KMO and TDO activity protects against neurodegenerative disease in an animal model, indicating that strategies targeted at two key points within the KP may have therapeutic relevance in HD, and possibly other neurodegenerative disorders.
authors.affiliation: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Susanna
authors.initials: S
authors.lastname: Campesan
authors.forename: Edward W
authors.initials: EW
authors.lastname: Green
authors.forename: Carlo
authors.initials: C
authors.lastname: Breda
authors.forename: Korrapati V
authors.initials: KV
authors.lastname: Sathyasaikumar
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
authors.forename: Charalambos P
authors.initials: CP
authors.lastname: Kyriacou
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000473:pathology*; D007736:Kynurenic Acid / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D007737:Kynurenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics
chemical_list: D018696:Neuroprotective Agents; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid