Eye colour mutations in the fruit-fly are being used to study degeneration of photoreceptor neurons, which may have relevance to conditions such as Huntington’s disease. Image taken using a light microscope. Credit: University of Leicester
JPEG IMAGES OF FRUIT-FLY BY LIGHT MICROSCOPE AND OF RESEARCHERS AVAILABLE FROM PRESSOFFICE@LE.AC.UK
Medical researchers may have uncovered a novel approach to treat an incurable and ultimately fatal neurodegenerative disease that affects hundreds of thousands of people.
Two international studies, one led by the University of Leicester, and the other a collaboration with Leicester led by scientists in the USA, hold out promise for slowing down the development of Huntington’s disease – and potentially, Alzheimer’s and Parkinson’s diseases. The research, which is in its early stages, represents an important milestone in understanding these debilitating conditions.
Huntington’s disease is a devastating inherited neurodegenerative disorder that is always fatal. The disorder of the central nervous system causes progressive degeneration of cells in the brain, slowly impairing a person’s ability to walk, think, talk and reason. Approximately 1 in 10,000 individuals are affected worldwide.
In the world-famous Department of Genetics at Leicester, the groups of Dr Flaviano Giorgini and Prof Charalambos Kyriacou found that by genetically targeting a particular enzyme in fruit-flies, kynurenine 3-monooxygenase or KMO, they arrested the development of the neurodegeneration associated with Huntington’s disease. Furthermore by directly manipulating metabolites in the KMO cellular pathway with drugs, they could manipulate the symptoms that the flies displayed.
The fruit-fly study, to be published in Current Biology on 7 June, was also aided by the groups of Prof Robert Schwarcz (Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore), who pioneered work in this area, and Dr Paul Muchowski (Gladstone Institutes, University of California, San Francisco). The two latter workers and Dr Giorgini have simultaneously published a paper in Cell, announcing a similar breakthrough in understanding the therapeutic relevance of KMO in transgenic mouse models of Huntington’s and Alzheimer’s diseases. http://www.gladstone.ucsf.edu/gladstone/site/publicaffairs/content/1/720
The fruit -fly research at Leicester took place over three years and was funded by the Huntington’s Disease Association and the CHDI Foundation, Inc. Dr Giorgini, who led the UK study, states, “This work provides the first genetic and pharmacological evidence that inhibition of a particular enzyme – KMO – is protective in an animal model of this disease, and we have also found that targeting other points in this cellular pathway can improve Huntington’s disease symptoms in fruit flies. This breakthrough is important as no drugs currently exist that halt progression or delay onset of Huntington’s disease. We are tremendously excited about these studies, as we hope that they will have direct ramifications for Huntington’s disease patients. Our work combined with the study in our companion publication in Cell, provides important confirmation of KMO inhibition as a potential therapeutic strategy for these individuals. As many KMO inhibitors are available, and more are being developed, it is hoped that such compounds can ultimately be tested in clinical trials for this as well as other neurodegenerative disorders.“
In Leicester the experiments were carried out by Drs Susanna Campesan, Edward Green, and Carlo Breda and in Baltimore, by Dr Korrapati Sathyasaikumar. The collaborating teams will continue their studies aimed at enhancing the development of medical intervention in Huntington’s and other neurodegenerative disorders.
Cath Stanley, Chief Executive of the Huntington’s Disease Association, said: “This is an exciting piece of research that will offer hope to the many people affected by Huntington’s disease.”
NOTE TO NEWSDESK
For more information contact:
Flaviano Giorgini, PhD
Lecturer in Mammalian Genetics
Department of Genetics
University of Leicester
Phone: 44 (0)116 252 3485
Below is a more scientific/technical briefing for the study by Dr Giorgini of the University of Leicester:
In general our research is focused on better understanding neurodegenerative diseases at a molecular level, with the hope that this information will inform therapeutic strategies for these disorders. This particular study is centred on the role of the kynurenine pathway in Huntington’s disease. The kynurenine pathway is the primary cellular route for tryptophan degradation in mammals, and generates several neuroactive metabolites. We have used a Drosophila melanogaster (fruit-fly) model of Huntington’s disease to interrogate the pathway by both genetic and pharmacological means in order to study the consequences on neurodegeneration. These fruit-flies exhibit many symptoms that recapitulate this disease, including locomotor problems, neurodegeneration, and shortened lifespan.
This work was carried out in order to better understand the role of kynurenine pathway metabolites in Huntington’s disease pathology and to validate the efficacy of targeting this pathway as a therapeutic strategy.
We found that both genetic and pharmacological inhibition of kynurenine 3-monooxygenase (KMO) reduces neurodegeneration in a fruit fly model of Huntington’s disease. We also find that targeting additional points in the kynurenine pathway can improve Huntington’s disease symptoms in flies. In all cases, we measured levels of the kynurenine pathway metabolites and found that levels of neuroprotective metabolites were increased relative to neurotoxic metabolites when less neurodegeneration was observed. Furthermore, we found that by feeding the flies neuroactive kynurenine pathway metabolites we can modulate neurodegeneration, highlighting the causative nature of these metabolites in this disease model.
This work provides the first genetic and pharmacological evidence that inhibition of KMO is protective in an amimal model of this disease. Furthermore, we find that inhibition of the enzyme tryptophan-2-3-dioxygenase (TDO) in this pathway is also protective, highlighting a novel candidate site for therapeutic targeting. Importantly we find that directly modulating metabolites in the pathway affects neurodegeneration. This work dovetails strongly with a collaborative sister publication in Cell directed by Dr Paul Muchowski. This study found that inhibition of KMO using a novel inhibitor ameliorates several important symptoms in mouse models of both Huntington’s disease and Alzheimer’s disease.
It is now seems timely to consider testing the efficacy of KMO inhibitors, and potentially inhibitors of other kynurenine pathway enzymes, in Huntington’s disease patients as well as sufferers from other neurodegenerative disorders.
The Huntington’s Disease Association
The Huntington’s Disease Association is a National Charity that strives to improve the quality of life for people affected by Huntington’s disease. More information about the Huntington’s Disease Association can be found at
About CHDI Foundation, Inc.
CHDI Foundation, Inc. is a privately-funded, not-for-profit, biomedical research organization that is exclusively dedicated to rapidly discovering and developing therapies that slow the progression of Huntington’s disease (HD). As a collaborative enabler, CHDI seeks to bring the right partners together to identify and address critical scientific issues and move drug candidates to clinical evaluation as quickly as possible. Our scientists work closely with a network of more than 600 researchers in academic and industrial laboratories around the world in the pursuit of these novel therapies, providing project management to ensure that our common goals remain in focus. More information about CHDI can be found at www.chdifoundation.org