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Investigating the role of gut microbiota in Parkinson’s disease using a C. elegans model

The aim of this project is to investigate the role of gut bacteria in Parkinson’s disease, a neurodegenerative disease characterized by loss of dopaminergic neurons.

A growing body of literature has demonstrated a bi-directional communication between the gut and the brain and the role of gut bacteria and their metabolites in modulating nervous system function 1,2. The complexity and size of the human microbiome makes it very difficult to tease apart the contributions of each bacterial species.

Caenorhabditis elegans is a microscopic nematode with a very simple nervous system consisting of only 302 neurons. Precisely 8 of these neurons are dopaminergic. Thanks to the transparency of C. elegans, we can label and observe its dopaminergic neurons in living animals, and assess their structural integrity using fluorescence microscopy or automated imaging platforms 3,4. C. elegans feeds on bacteria, which means its gut microbiota can be determined by the type of food we provide. Therefore, it offers an ideal model to test how the metabolic activity of the microbiome affects the nervous system.

The project will investigate candidate bacterial species found in the human gut for their effect on dopaminergic neurons in sensitised C. elegans models of neurodegeneration. Special focus will be given to bacteria differentially present in Parkinson’s patients as well as probiotic bacteria. Bacterial ‘hits’ that modulate the severity of neurodegenerative phenotypes, will be genetically dissected to determine the metabolic pathways responsible for the observed effects. The most interesting candidate bacteria, pathways or molecules will be validated in a novel rat model of Parkinson’s in the laboratory of Dr. Tilo Kunath.

1. Mayer, E.A., Knight, R., Mazmanian, S.K., Cryan, J.F., and Tillisch, K. (2014). Gut microbes and the brain: paradigm shift in neuroscience. J. Neurosci. 34, 15490–15496.

2. Sampson, T.R., Debelius, J.W., Thron, T., Janssen, S., Shastri, G.G., Ilhan, Z.E., Challis, C., Schretter, C.E., Rocha, S., Gradinaru, V., et al. (2016). Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell 167, 1469–1480.e12.

3. Doitsidou, M., Flames, N., Lee, A.C., Boyanov, A., and Hobert, O. (2008). Automated screening for mutants affecting dopaminergic-neuron specification in C. elegans. Nat. Methods 5, 869–872.

4. Nagarajan, A., Ning, Y., Reisner, K., Buraei, Z., Larsen, J.P., Hobert, O., and Doitsidou, M. (2014). Progressive degeneration of dopaminergic neurons through TRP channel-induced cell death. J. Neurosci. 34, 5738–5746.

Supervision team

Dr Maria Doitsidou and Dr Tilo Kunath

Maria Doitsidou research group

+44 (0) 131 651 1727

maria.doitsidou@ed.ac.uk

Further information

Centre for Integrative Physiology website