The role of the metabotropic glutamate receptor type 5 in motor neuron disease (MND)

A major focus of research within the internationally recognised Sheffield Institute for Translational Neuroscience (SITraN) is to understand the pathways leading to neurodegeneration, and to identify new approaches which will protect neurons. This PhD project will investigate the role of the metabotropic glutamate receptor 5 (mGlu5) in neurodegeneration in motor neuron disease (MND). We are collaborating with a world leading Biotech company, Sosei Heptares, and using their novel mGlu5 antagonist [1, 2] to dissect the role of mGlu5 in a range of cutting edge in vitro and in vivo disease models of MND [3, 4]. The project has a significant translational angle and the generated data will support potential future therapeutic trials in neurodegenerative diseases such as MND.

The PhD candidate would work with Sosei Heptares’ mGlu5 antagonist and other chemical probes in our model systems of MND, both in vitro (astrocyte and MN cultures [4]) and in vivo (SOD1 G93A mice [3] TDP-43 Q331K mice [5] and C9ORF72 BAC transgenic mice [6]) to dissect disease mechanisms and pathways. Both in vivo and in vitro electrophysiology will be a major component of the work. The candidate will also have the opportunity to be placed for a period within Sosei Heptares, providing unique training in Industrial drug development..

1. Christopher, J.A., et al., Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem, 2015. 58(16): p. 6653-64.
2. Dore, A.S., et al., Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature, 2014. 511(7511): p. 557-62.
3. Mead, R.J., et al., Optimised and Rapid Pre-clinical Screening in the SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis (ALS). PLoS One, 2011. 6(8): p. e23244.
4. Meyer, K., et al., Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci U S A, 2014. 111(2): p. 829-32.
5. Arnold, E.S., et al., ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A, 2013. 110(8): p. E736-45.
6. Liu, Y., et al., C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron, 2016. 90(3): p. 521-34.