Identification of Novel Mechanisms Supporting Axon Survival and Investigation of their Therapeutic Potential

Summary

Programmed axon death is a widespread and completely preventable mechanism in injury and disease (Coleman and Hoke, Nat Rev Neurosci, 2020). Mouse and Drosophila studies define a molecular pathway involving activation of SARM1 NADase and its prevention by NAD synthesising enzyme NMNAT2. Loss of axonal NMNAT2 causes its substrate, NMN, to accumulate and activate SARM1, driving loss of NAD(P) and changes in ATP, ROS and calcium.  

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 these animal studies, recent data indicate that human gene variants in programmed axon death genes associate with neurological disorders. Loss-of-function mutations in NMNAT2 are a cause of a rare form of polyneuropathy, which may serve as a model also for more common peripheral neuropathies. Gain-of-function mutations in SARM1 have been associated with the most common form of motor neuron disease (ALS) (Gilley et al, eLife, 2021) and with a retinal disorder. As a consequence of this work, multiple Pharmaceutical companies are targeting SARM1 inhibition therapeutically.

Project aims 

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.

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

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

Opportunities

This opportunity is open to PhD applicants.