The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
The Kynurenine Pathway Modulates Neurodegeneration in a Drosophila Model of Huntington's Disease
Open accessAbstract
Summary 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.
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Cites
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Huntington's disease: from molecular pathogenesis to clinical treatment
Ross, C. A., & Tabrizi, S. J. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70245-3 · Cited by 1,743
Quinolinic Acid: An Endogenous Metabolite That Produces Axon-Sparing Lesions in Rat Brain
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Self-citationHistone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
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Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS
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Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration
Zwilling, D., Huang, S.-Y., Sathyasaikumar, K. V., Notarangelo, F. M., Guidetti, P., Wu, H.-Q., Lee, J., Truong, J., Andrews-Zwilling, Y., Hsieh, E. W., et al. (2011) · Cell · doi:10.1016/j.cell.2011.05.020 · Cited by 515
Self-citationFoster, A. C., Vezzani, A., French, E. D., & Schwarcz, R. (1984) · Neuroscience Letters · doi:10.1016/0304-3940(84)90050-8 · Cited by 434
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Self-citationThe kynurenine pathway of tryptophan degradation as a drug target
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Self-citationPresynaptic kynurenate‐sensitive receptors inhibit glutamate release
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Cited by
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641
Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond
Platten, M., Nollen, E. A. A., Röhrig, U. F., Fallarino, F., & Opitz, C. A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0016-5 · Cited by 1,586
Kynurenines in the mammalian brain: when physiology meets pathology
Schwarcz, R., Bruno, J. P., Muchowski, P. J., & Wu, H.-Q. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3257 · Cited by 1,530
Self-citationNAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W., Huang, C., Huber, P. E., Zhou, X., Li, C., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,052
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790
Metadata
- Authors
- Campesan, S., Green, E. W., Breda, C., Sathyasaikumar, K. V., Muchowski, P. J., Schwarcz, R., Kyriacou, C. P., & Giorgini, F.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 21
- Issue
- 11
- Pages
- 961-966
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W1974769584
- Cited by
- 258
- References
- 30
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Campesan, S., Green, E. W., Breda, C., Sathyasaikumar, K. V., Muchowski, P. J., Schwarcz, R., Kyriacou, C. P., & Giorgini, F. (2011). The Kynurenine Pathway Modulates Neurodegeneration in a Drosophila Model of Huntington's Disease. Current Biology. https://doi.org/10.1016/j.cub.2011.04.028
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