The Roles of Programmed Axon Death in Human Disease

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 so far points to roles in polyneuropathies and motor neuron disease. It is clear from animal studies that there are wider roles in disease with implications for peripheral neuropathies, glaucoma, viral encephalitis, traumatic brain injury, Parkinson’s disease and possibly multiple sclerosis. However, all models have limitations so it is important to gain further insights directly from human studies.

Project aims 

We and others have identified a number of naturally-occurring human gene variants for both SARM1 (gain- and loss-of-function; GoF and LoF) and NMNAT2 (LoF) and identification of more is in progress. 

With the continual growth of human genome and exome sequencing studies (UK Biobank, 100,000 Genomes Project, Finngen, Regeneron Million Exomes Project, gnomAD) there are major opportunities to identify association between these functional variants and specific human diseases. 

The successful candidate will carry out bioinformatic analysis of these and other genomic databases together with hiPSC-derived neuron studies to test for SARM1 activation downstream of other known causes of disease. Other methods used will include molecular cloning, site-directed mutagenesis, phase contrast and fluorescent microscopy and enzyme assays. 

The outcome should help to inform ongoing drug development studies in the Pharma industry about the most appropriate diseases in which to perform clinical trials and about personalised medicine uses of such drugs for patients most likely to benefit.
 

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

Ademi et al, Sci Rep 12: 13846

Huppke et al, Exp Neurol 320: 112958

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.