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SUMMARY:Programmed axon death: from animal models into human disease - Pro
 fessor Michael Coleman\, Department of Clinical Neurosciences
DTSTART:20230131T160000Z
DTEND:20230131T170000Z
UID:TALK194476@talks.cam.ac.uk
CONTACT:Dr Dervila Glynn
DESCRIPTION:*Theme: Beyond the Neuron: Glia\, vascular and immune cells*\n
 \n*Abstract:* Programmed axon death is a widespread and completely prevent
 able mechanism in injury and disease. Mouse and Drosophila studies define 
 a molecular pathway involving activation of SARM1 NADase and its preventio
 n by NAD synthesising enzyme NMNAT2. Loss of axonal NMNAT2 causes its subs
 trate\, NMN\, to accumulate and activate SARM1\, driving loss of NAD(P) an
 d changes in ATP\, ROS and calcium.  \n\nAnimal models caused by genetic m
 utation\, toxins\, viruses or metabolic defects can be alleviated by block
 ing programmed axon death\, for example models of CMT1B\, chemotherapy-ind
 uced peripheral neuropathy (CIPN)\, rabies and diabetic peripheral neuropa
 thy (DPN). The perinatal lethality of NMNAT2 null mice is completely rescu
 ed\, restoring a normal\, healthy lifespan.\n\nAnimal models lack the gene
 tic and environmental diversity present in human populations and this is p
 roblematic for modelling gene-environment combinations\, for example in CI
 PN and DPN\, and identifying rare\, pathogenic mutations. Instead\, by tes
 ting human gene variants in WGS datasets for loss- and gain-of-function\, 
 we identified enrichment of rare SARM1 gain-of-function variants in sporad
 ic ALS\, despite previous negative findings in SOD1 transgenic mice. \n\nW
 e have shown in mice that heterozygous SARM1 loss-of-function is protectiv
 e from a range of axonal stresses and that naturally-occurring SARM1 loss-
 of-function alleles are present in human populations. This enables new app
 roaches to identify disorders where blocking SARM1 may be therapeutically 
 useful\, and the existence of two dominant negative human variants in heal
 thy adults is some of the best evidence available that drugs blocking SARM
 1 are likely to be safe.\n\nFurther loss- and gain-of-function variants in
  SARM1 and NMNAT2 are being identified and used to extend and strengthen t
 he 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. \n\n*Biography:* Michael Coleman is the van Geest 
 Professor of Neuroscience at Cambridge UK\, studying mechanisms of axon de
 generation and synapse loss. He previously led research groups in this fie
 ld 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 pathw
 ay of proteins influencing axon degeneration in a wide range of disease mo
 dels. Their finding that ablation of SARM1 can rescue axons permanently fo
 llowing ablation of its upstream regulator NMNAT2 has generated significan
 t Pharma interest the pathway. Their recent work has used human genetics t
 o 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 acad
 emics and efforts to modernise and improve the culture of academic researc
 h.\n\nRegister in advance for this meeting: https://us02web.zoom.us/meetin
 g/register/tZUpduqgrzopGNZAHg60etdvveSARuIgCLeX\n\nAfter registering\, you
  will receive a confirmation email containing information about joining th
 e meeting.\n\n
LOCATION:Register on Zoom - link in abstract
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