The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease

Curr Biol. 2011 Jun 7;21(11):961-6. doi: 10.1016/j.cub.2011.04.028.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / metabolism
  • Disease Models, Animal
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Huntington Disease / pathology*
  • Kynurenic Acid / chemistry
  • Kynurenic Acid / metabolism
  • Kynurenic Acid / therapeutic use
  • Kynurenine / analogs & derivatives
  • Kynurenine / chemistry
  • Kynurenine / metabolism*
  • Kynurenine 3-Monooxygenase / antagonists & inhibitors
  • Kynurenine 3-Monooxygenase / chemistry
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / metabolism*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / metabolism
  • Tryptophan / chemistry
  • Tryptophan / metabolism
  • Tryptophan Oxygenase / antagonists & inhibitors
  • Tryptophan Oxygenase / chemistry
  • Tryptophan Oxygenase / genetics


  • Neuroprotective Agents
  • 3-hydroxykynurenine
  • Kynurenine
  • Tryptophan
  • Tryptophan Oxygenase
  • Kynurenine 3-Monooxygenase
  • Kynurenic Acid