Programmed axon death: from animal models into human disease | Professor Michael Coleman | Cam Neuro

Programmed axon death: from animal models into human disease Professor Michael Coleman Theme: Beyond the Neuron Abstract: Programmed axon death is a widespread and completely preventable mechanism in injury and disease. Mouse and Drosophila studies define a molecular pathway involving activation of SARM1 NA Dase 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 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. Animal models lack the genetic and environmental diversity present in human populations and this is problematic for modelling gene-environment combinations, for example in CIPN and DPN , and identifying rare, pathogenic mutations. Instead, by testing human gene variants in WGS datasets for loss- and gain-of-function, we identified enrichment of rare SARM1 gain-of-function variants in sporadic ALS , despite previous negative findings in SOD1 transgenic mice. We have shown in mice that heterozygous SARM1 loss-of-function is protective from a range of axonal stresses and that naturally-occurring SARM1 loss-of-function alleles are present in human populations. This enables new approaches to identify disorders where blocking SARM1 may be therapeutically useful, and the existence of two dominant negative human variants in healthy adults is some of the best evidence available that drugs blocking SARM1 are likely to be safe. Further loss- and gain-of-function variants in SARM1 and NMNAT2 are being identified and used to extend and strengthen the evidence of association with neurological disorders. We aim to identify diseases, and specific patients, in whom SARM1 -blocking drugs are most likely to be effective. Biography: Michael Coleman is the van Geest Professor of Neuroscience at Cambridge UK, studying mechanisms of axon degeneration and synapse loss. He previously led research groups in this field at the Babraham Institute, Cambridge, Cologne, Germany and Oxford, UK. His group identified the first protein known to delay degeneration of injured axons (Wallerian degeneration) leading to the discovery of a pathway of proteins influencing axon degeneration in a wide range of disease models. Their finding that ablation of SARM1 can rescue axons permanently following ablation of its upstream regulator NMNAT2 has generated significant Pharma interest the pathway. Their recent work has used human genetics to link this pathway to polyneuropathies and sporadic ALS , and potentially other disorders, directly in humans. Alongside his research interests, Professor Coleman has a growing interest in coaching and mentoring of academics and efforts to modernise and improve the culture of academic research. About this series: The Cambridge Neuroscience Interdisciplinary Seminar Series provides a forum for neuroscientists across Cambridge and beyond to discuss contemporary and interdisciplinary research topics and issues. The seminars are open to both members of the University, external academics and members of the public. We have tried to reflect the diversity of people’s interests at the University with our programme, and the breadth of the research taking place in Cambridge. Registration and more details are available here: http://talks.cam.ac.uk/show/index/125062 For more information on Cambridge Neuroscience, please see www.neuroscience.cam.ac.uk or follow us on Twitter @CamNeuro