Preventable axon degeneration in human disease (360G-Wellcome-220906_Z_20_Z)

Programmed axon degeneration (or Wallerian degeneration; WD) is a preventable and druggable mechanism of axon loss. WD is well-characterised in animals and highly conserved. Blocking WD alleviates axon loss and symptoms in multiple disease models, suggesting a common, downstream mechanism. Human data are essential to confirm the role of WD in specific human diseases, ensuring drugs under development are tested in highly-relevant disorders and patients. We reported mutations in rare human axonopathies that aberrantly activate WD, and lifelong rescue of a related mouse model. Our programme determines the wider involvement of WD in rare and common human disorders, specifically peripheral neuropathies and ALS, where axon degeneration is important. We use online resources (100,000 Genomes, Project MinE, UK Biobank, etc.) and targeted sequencing of well-phenotyped cohorts and test roles of gene variants in causation, risk and severity. We determine their functional impact using complementary human iPSC and mouse modelling and develop specific biomarkers of WD for clinical samples. This project will provide insight into pathogenic mechanisms and a firm platform for developing and testing therapeutics. Our team, a world leader in Wallerian degeneration and leading neurogeneticists in rare and common neuropathies and human iPSC modelling, is uniquely placed to deliver this.