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Role of the microbiome in neurodegenerative disease

Primary Supervisor: Professor Julian Ketley, Department of Genetics and Genome Biology

Secondary Supervisor: Professor Flaviano Giorgini

PhD project title: Role of the microbiome in neurodegenerative disease

University of Registration: University of Leicester

Project outline:

The human microbiome is essential for human health as it is crucial for the development of immunity, tissue development, host metabolism and protection from various infectious diseases. The microbiome is an important component of host physiology and dysbiosis can cause changes in metabolism that impact on health.

Microbe-derived molecules modulate organ physiology directly or through mechanisms that regulate signalling by hormones or nerves, as happens in the gut-brain axis. The gut microbiota has been linked with multiple brain diseases, such as autism spectrum disorder, depression, schizophrenia and neurodegenerative diseases. One of the main pathways related with the physiology of the gut-brain axis is tryptophan metabolism, with serotonin, a well-known mediator of the communication between brain and gut. Tryptophan is involved in another metabolic pathway, the kynurenine pathway (KP). This metabolic pathway has been linked to neurodegenerative diseases such as Huntington’s (HD), Alzheimer’s (AD) and Parkinson’s via the actions of three neuroactive metabolites: 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). 3-HK and QUIN are neurotoxic via generation of free radicals and overstimulation of excitatory glutamate receptors, respectively. KYNA, on the other hand, is neuroprotective by counteracting these toxic insults.

The project proposed here will address the hypothesis that KP metabolites produced by the gut microbiota directly influence the phenotypes of neurodegenerative disease, specifically HD. Drosophila melanogaster, the fruit fly, will be used as the model host system due to the ease of genetic manipulation of the host and ability to manipulate the intestinal microbiome. The less complex Drosophila nervous system has similarities with human brain, has a genome which is easier to manipulate and a short life cycle. Drosophila models of neurodegenerative diseases are well-established, including polyglutamine diseases such as HD. A well-defined set of Drosophila transgenic lines are available at Leicester that form a well-developed model to study HD and associated factors.

Objectives:

  1. Investigate the contribution of bacteria in the gut microbiota in modulating HD through kynurenine pathway metabolites
  2. Investigate how the altered production of kynurenine pathway metabolites by intestinal bacteria modulates the phenotype of HD model flies
  3. Determine if the feeding of elements of the kynurenine pathway alters the microbiota and/or phenotype of Drosophila lines

References:

  1. The kynurenine pathway and neurodegenerative disease. Maddison DC, Giorgini F. 2015. Semin Cell Dev Biol. 40:134-41.
  2. The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington's disease. Campesan S1, Green EW, Breda C, Sathyasaikumar KV, Muchowski PJ, Schwarcz R, Kyriacou CP, Giorgini F. 2011. Curr Biol. 21(11):961-6
  3. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites. Breda C, Sathyasaikumar KV, Sograte Idrissi S, Notarangelo FM, Estranero JG, Moore GG, Green EW, Kyriacou CP, Schwarcz R, Giorgini F. 2016. Proc Natl Acad Sci U S A. 113(19):5435-40.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology

Techniques that will be undertaken during the project: 

  • Molecular biology involving gene cloning and protein expression strategies.
  • Generation and maintenance of transgenic fly lines and bacterial strains
  • Drosophila genetics and viability/behavioural analyses
  • Metabolomics
  • Bioinformatics

Contact: Professor Julian Ketley, University of Leicester