Probing the mechanism of programmed axon death using protein design

Summary

Programmed axon death is an intrinsic death programme in axons, executed by the NAD degrading enzyme SARM1 and regulated by the NAD synthesising enzyme NMNAT2. The programme can be activated by axon injury, gene mutation, metabolic perturbations, toxins and viruses and is involved in many neurodegenerative diseases. 

Human genetics points to roles in polyneuropathies and motor neuron disease, while animal studies strongly suggest wider relevance also in peripheral neuropathies, glaucoma, viral encephalitis, traumatic brain injury, Parkinson’s disease and possibly multiple sclerosis. With the recent success of a Phase I clinical trial for SARM1 inhibitors and others in development, it is an important time to develop new tools to study the pathway further.

Project aims 

SARM1 is a modular protein composed of ARM, SAM and TIR domains. CryoEM and crystal structures of each domain and the holoprotein are available, both in its inactive and activated forms. Against this background the aim of this project is to perform rational design of variant forms of SARM1, or hybrids with reporter molecules, to act as tools for studying SARM1 activation, stability, enzyme activity and post-translational modification. 

The successful candidate will gain skills in molecular cloning, site directed mutagenesis, enzyme assays, primary and hiPSC-derived neuron cell cultures, transfection and structural analysis and will contribute to both basic biological knowledge and drug discovery efforts in this area.  
Our research group has a strong collaborative and supportive culture with many opportunities for conference participation and personal and professional development.

Suggested Reading

Coleman and Hoke, Nat Rev Neurosci 21: 183-196 (2020)

Gilley et al, eLife 10: e70905

Loreto et al, Neurobiol Dis 213: 106986

https://www.sciencewithoutanguish.com

Contact details

Michael Coleman - mc469@cam.ac.uk - Coleman Laboratory - Clinical Neurosciences 

Opportunities

This opportunity is open to PhD or MPhil applicants.