Neil McDonald

 

Identification and characterisation of new GDNF signalling modulators

Glial cell line-derived neurotrophic factor (GDNF) is a midbrain dopaminergic neuron survival factor that uses multiple receptor systems to signal. Components of GDNF-dependent signalling include the receptor tyrosine kinase RET, GFRa1, NCAM, syndecans and other as yet unidentified cell surface receptors (Ref 1). Functional evidence supports important roles for GDNF in the central nervous system and suggest a particular relevance for neurodegenerative and neuropsychiatric diseases. My lab has explored the structural basis for GDNF-signalling and probed molecular recognition events involved and how they translate to receptor activation (Ref 2). Our recent results have lead us to consider how to translate our structural findings to develop tools and reagents to manipulate GDNF signalling in cells and animal models of disease. Our work has also opened up avenues to uncover new signalling partners and receptors whose existence has been suggested by cell-based work.

The laboratory has an opening for a PhD project that will broadly focus on manipulating the adhesive and neurotrophic properties of GDNF. Examples of elements of the project that might be available in the research group include: (1) screening for small molecule potentiators/mimetics of GDNF-GFRa1 and defining their mode-of-action (2) directed evolution approaches to identify more potent GDNF-GFRa1 agonists with therapeutic applications for different types of stem cells (3) characterise available biologicals developed in the lab for their potency in either stimulating or blocking GDNF signalling pathways. Generating a toolbox of reagents able to manipulate GDNF signalling outputs would be clinically useful as well as provide important chemical biology tools (4) develop labelling methods such as BioID and sHRP to identify novel proximal partners of GDNF complexes involved in neurogenesis and determine their three-dimensional structure. The precise project will be decided on in consultation with the supervisor.

1. Ibáñez, C. F. and Andressoo, J.-O. (2017)
Biology of GDNF and its receptors - Relevance for disorders of the central nervous system.
Neurobiology of Disease 97: 80-89. PubMed abstract

2. Goodman, K. M., Kjær, S., Beuron, F., Knowles, P. P., Nawrotek, A., Burns, E. M., Purkiss, A. G., George, R., Santoro, M., Morris, E. P. and McDonald, N. Q. (2014)
RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association.
Cell Reports 8: 1894-1904. PubMed abstract