PNAS: Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites
Researchers at the University of Leicester and the University of Maryland in the US have studied a group of metabolites that work together to influence nerve cell health. Using genetic and chemical approaches in fruit flies, the researchers found that blocking one of the chemicals in the group could protect against neurodegeneration in flies bred to show features of Alzheimer’s disease, Huntington’s disease and Parkinson’s.
The team studied a group of metabolites that work together in a chain of events called the ‘kynurenine pathway’. Some members of this group have previously been linked to neurodegeneration, and their activity can be regulated by a protein called tryptophan-2,3-dioxygenase (TDO). To study this process in more detail, the researchers used fruit flies that had been bred to develop features of either Huntington’s disease, Alzheimer’s or Parkinson’s. The flies bred to show features of Alzheimer’s were genetically altered to develop a build-up of a protein called amyloid, which is also seen in the brains of people with the disease.
The researchers blocked TDO in their fly models of neurodegeneration, using either genetic approaches or a chemical inhibitor. Blocking TDO made flies live longer and move better and protected against nerve cell damage. The authors suggest that TDO inhibitors should be considered as a potential new treatment strategy for a range of neurodegenerative diseases.
Dr Laura Phipps of Alzheimer’s Research UK, said:
“While fruit flies cannot re-create the full complexity of diseases like Alzheimer’s and Parkinson’s in humans, they can provide a starting point to identify important mechanisms involved in nerve cell health. This study identifies a metabolic chain of events that can be chemically blocked to protect against nerve cell damage in flies. The findings of the study don’t tell us that blocking this process could slow or stop Alzheimer’s in people, but forms the basis for further research into the role of these metabolites in the disease. TDO inhibitors are already in development for their potential to treat cancer, and these findings suggest that these drugs could be investigated for possible benefits in neurodegenerative diseases too.
“Laboratory based research in flies and mice is vital to help researchers identify genes and proteins that play a key role in the diseases that cause dementia. It’s now crucial that our increasing knowledge of the biology behind diseases like Alzheimer’s is translated as quickly as possible into benefits for patients. Alzheimer’s Research UK is investing heavily in early-phase drug discovery projects that link academic scientists with drug discovery expertise, with the goal of fast-tracking the search for effective new treatments for dementia.”
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