Completed Brain & Nervous System Genetics & Molecular Biology

Preventable axon degeneration in human disease

Funder Wellcome Charity-funded
Associated organisations Johns Hopkins University · University College London · University of Cambridge · University of Oxford Europe PMC affiliations are not treated as award recipients or mapped locations.
Funding £3.6M
Period Apr 2021 — Mar 2026

In plain English

AI plain-English summary

Nerve cells can self-destruct through a specific, preventable process called programmed axon degeneration, and this team is working out exactly which human diseases trigger it. This matters because axons—the long fibres that carry signals between nerve cells—are lost in many debilitating conditions, from rare inherited neuropathies to motor neurone disease (ALS). While scientists have known for decades that blocking this self-destruct mechanism protects nerves in animals, no one has yet confirmed which human diseases actually use it. Without that knowledge, drug developers cannot know which patients to test their treatments on. The researchers will analyse genetic data from large resources such as the 100,000 Genomes Project and UK Biobank, plus sequence DNA from well-characterised patient groups. They will then test how specific gene variants affect axon survival using human stem-cell-derived neurons and mouse models, and develop biomarkers to detect active axon degeneration in patient blood or tissue. If successful, this work will identify the right patient populations for emerging drugs that block axon degeneration. It could also reveal new drug targets for common conditions where nerve loss is a major problem, such as diabetic neuropathy or chemotherapy-induced nerve damage.

View original technical description
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.

View the original record at the funder ↗

Researchers

Ahmet Hoke (EPMC Awardee)David Bennett (EPMC Awardee)Mary Reilly (EPMC Awardee)Michael Philip Coleman (EPMC Awardee)

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Original classification

Collaborative Award in Science

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