Please use this identifier to cite or link to this item:
Title: The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease.
Authors: Campesan, S
Green, EW
Breda, C
Sathyasaikumar, KV
Muchowski, PJ
Schwarcz, R
Kyriacou, CP
Giorgini, Flaviano
First Published: 7-Jun-2011
Citation: CURR BIOL, 2011, 21 (11), pp. 961-966
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.
DOI Link: 10.1016/j.cub.2011.04.028
eISSN: 1879-0445
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Genetics

Files in This Item:
There are no files associated with this item.

Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.