Study in flies could have major implications for human disease.
Alzheimer’s and Parkinson’s disease are the two most common neurodegenerative disorders worldwide and cause untold suffering to millions of patients and their families. Treatments for these diseases are limited, and no cures exist. Now, a new study describes an innovative strategy that reverses symptoms in these neurodegenerative diseases – at least in fruit flies which had been genetically altered to model the diseases.
“The novel approach we used has significant translational implications,” said one of the lead authors, Robert Schwarcz, a researcher in the Department of Psychiatry at the University of Maryland School of Medicine. “If we can duplicate these effects in patients, we could benefit a lot of people.”
Schwarcz collaborated with geneticist Flaviano Giorgini at the University of Leicester in England. The study was published today in the journal Proceedings of the National Academy of Sciences.
The researchers focused on metabolites related to the amino acid tryptophan. When tryptophan degrades in the body, it breaks down into several compounds that have biological activities in the nervous system. One of these, 3-hydroxykynurenine (3-HK), has neurotoxic properties whereas another, named kynurenic acid (KYNA), has the ability to prevent nerve cell degeneration. The relative abundance of these two compounds in the brain may be critical in Alzheimer’s and Parkinson’s disease, and also Huntington’s disease.
Schwarcz, Giorgini and their colleagues gave the insects a chemical that selectively inhibits tryptophan-2,3-dioxygenase (TDO), an enzyme that controls the relationship between 3-HK and KYNA. This treatment shifted metabolism towards more KYNA, improved movement, and lengthened lifespan in the fly models of the diseases.
“A key finding of our study is that we can improve “symptoms” in fruit fly models of Alzheimer’s and Parkinson’s disease by feeding them a drug-like chemical,” said another co-author, Carlo Breda of the University of Leicester. “Our experiments have identified TDO as a very promising new drug target.”
The next steps will involve testing of the new concept in humans and to examine whether the treatment works for neurodegenerative diseases.
About this genetics research
Source: David Kohn – University of Maryland School of Medicine Image Source: The image is in the public domain. Original Research: Full open access research for “Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites” 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, and Flaviano Giorgini in PNAS. Published online April 25 2016 doi:10.1073/pnas.1604453113
Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites
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.
“Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites” 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, and Flaviano Giorgini in PNAS. Published online April 25 2016 doi:10.1073/pnas.1604453113