Identification of novel mechanisms supporting axon survival with therapeutic potential in neurological disorders

Summary

Programmed axon death is a widespread and completely preventable mechanism in injury and disease (Coleman and Hoke, Nat Rev Neurosci, 2020). It is controlled by a molecular pathway involving activation of SARM1 NADase and its prevention by NAD synthesising enzyme NMNAT2. 

Animal models caused by genetic mutation, toxins, viruses or metabolic defects can be alleviated by blocking programmed axon death, for example models of CMT1B, chemotherapy-induced peripheral neuropathy (CIPN), rabies and diabetic peripheral neuropathy (DPN). The perinatal lethality of NMNAT2 null mice is completely rescued, restoring a normal, healthy lifespan.

In addition to animal studies, recent data reveal human gene variants in programmed axon death genes associated with neurological disorders. Loss-of-function in NMNAT2 causes a rare polyneuropathy, while gain-of-function in SARM1 associates with motor neuron disease (ALS) (Gilley et al, eLife, 2021) and retinal disease. As a consequence, multiple Pharmaceutical companies are targeting SARM1 inhibition therapeutically.

Our data indicate that there are compensatory mechanisms that enable neurons and their axons to survive for years or decades even when NMNAT2 is low or SARM1 function is high. We have identified several candidate mechanisms for these compensatory mechanisms which, once we understand them in more detail, could form the basis of highly effective therapies for multiple neurological disorders.

Project aims

The aim of this studentship will be to investigate these mechanisms and to test their therapeutical potential. Techniques to be used include human iPSC-derived neuronal cultures, site-directed mutagenesis and molecular cloning, phase contrast and fluorescence microscopy, microinjection of neurons in culture and mass spectrometry.

We work closely with collaborating groups in the USA and Italy, who there may be opportunities to visit. 

Contact details

Professor Michael Coleman - mc469@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD