A spectrum of axon vulnerability in the human population and its underlying causes

This project will quantify the degree of intrinsic variation in the vulnerability of human axons to a range of external stresses, and test the hypothesis that a well-understood and blockable mechanism of axon death, extensively studied in our laboratory, underlies some of this variation. Research in animal and cell culture models has identified two proteins whose sequence and expression level profoundly influence axon survival. SARM1 is a prodegenerative NADase enzyme, whose activation rapidly kills axons. It has an upstream regulator, NMNAT2, which synthesises NAD and prevents SARM1 activation in healthy axons. Together, these proteins determine a spectrum of axon vulnerability whose consequences range from death at or before birth, due to widespread axon growth failure, to a remarkable ability of physically transected axons to survive ten times longer than normal. Both proteins are now known to be involved in human axonal diseases, including peripheral neuropathies and motor neuron disease, and both genetic and toxic mechanisms can cause disease through each of these proteins. The successful candidate will use human iPSC-derived neuronal cultures and human nerve biopsies to determine the degree of variability of these proteins, their metabolic substrates and products, and how these influence human axon vulnerability including on exposure to toxins known to impact this mechanism. Methods used include working with pluripotent stem cells and human tissue, cell culture, phase contrast, epifluorescent and confocal microscopy, antisense oligonucleotide technologies and collaboration with experts in bioinformatics and human genetics in both academia and industry. The work will contribute to the identification of neurological diseases, and specific patients, who are likely to benefit the most from drugs under development.