Two enzymes that play an important role in the pathogenesis of neurodegeneration, and whose inhibition was seen to improve disease symptoms in fruit fly models, have been identified. Moreover, inhibition of one of these enzymes with a drug-like compound was found to reverse movement defects in the flies characteristic of diseases like Parkinson’s.
The study, by researchers at University of Leicester and University of Maryland School of Medicine, is titled “Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites” and published in Proceedings of the National Academy of Sciences of the USA.
“The two most common neurodegenerative disorders worldwide are Alzheimer’s and Parkinson’s disease. The treatment options for these diseases are limited, and to date no cures exist. Our hope is that by improving our knowledge of how these nerve cells become sick and die in the brain, we can help devise ways to interfere with these processes, and thereby either delay disease onset or prevent disease altogether,” Flaviano Giorgini, the study’s senior author and a professor in the Department of Genetics at Leicester, said in a news release.
Previous research had shown that metabolites from the kynurenine pathway (KP) of tryptophan degradation are closely linked to the development of several neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s. Moreover, recent work has also shown that strategic inhibition of two regulatory enzymes in this pathway, kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO), may have therapeutic effects. Scientific evidence suggests that the efficacy of KMO inhibition is due to the normalization of an imbalance between harmful and toxic metabolites and the neuroprotective metabolites of the KP pathway. The protective benefits of TDO inhibition, however, are still unclear.
Researchers conducted studies on fruit fly models (Drosophila melanogaster) of neurodegenerative diseases, and demonstrated that inhibition of either TDO or KMO led to significant improvement in disease pathology in the insects. Specifically, Parkinson’s flies were seen to have a longer lifespan and showed a reversal in movement dysfunctions.
Moreover, a drug-like chemical was used to inhibit TDO and found to allieviate “symptoms” in the flies, the researchers said, indicating a neuroprotective function in these models.
“We are excited by these results, as they suggest that TDO and KMO inhibition could be a general strategy employed to improve symptoms in a myriad of neurodegenerative disorders, not just Parkinson’s and Alzheimer’s,” Professor Giorgini said. “Indeed, five years ago we first showed that these manipulations could improve ‘symptoms’ in Huntington’s disease model flies, so our next step is to validate our work in mammalian models and ultimately to see if such drugs could be helpful to patients in clinical trials.”
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