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Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

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posted on 2016-05-11, 12:25 authored by Carlo Breda, Korrapati V. Sathyasaikumar, Shama Sograte Idrissi, Francesca M. Notarangelo, Jasper G. Estranero, Gareth G. L. Moore, Edward W. Green, Charalambos P. Kyriacou, Robert Schwarcz, Flaviano Giorgini
Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.

Funding

C.B. was supported by grants from the CHDI Foundation and Parkinson’s UK (to F.G. and C.P.K.). F.G. and C.P.K. also acknowledge grants from the Medical Research Council and the Biotechnology and Biological Sciences Research Council for valuable infrastructure supporting this work. Work in the R.S. laboratory was supported by NIH Grant R01-NS057715.

History

Citation

Proceedings of the National Academy of Sciences, 2016, 113 (9), pp. 5435-5440

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics

Version

  • AM (Accepted Manuscript)

Published in

Proceedings of the National Academy of Sciences

Publisher

National Academy of Sciences

eissn

1091-6490

Acceptance date

2016-03-28

Copyright date

2016

Available date

2016-05-11

Publisher version

http://www.pnas.org/content/113/19/5435

Language

en

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