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SUMMARY:Using human genetics to define a spectrum of axon vulnerability - 
 Professor Michael Coleman from Department of Clinical Neurosciences\, Camb
 ridge Biomedical Campus 
DTSTART:20220609T130000Z
DTEND:20220609T140000Z
UID:TALK174692@talks.cam.ac.uk
CONTACT:Caroline Newnham
DESCRIPTION:Studies from our group and others in model organisms\, especia
 lly mice and Drosophila\, have defined a molecular signalling pathway regu
 lating axon survival after injury\, termed programmed axon death. The same
  pathway can be activated by gene mutation\, toxins and some viruses. At i
 ts core are the prodegenerative enzyme SARM1 and its upstream regulator\, 
 NMNAT2\, which is essential for axon survival. Both enzymes regulate level
 s of NAD and related metabolites. Loss-of-function mutation of NMNAT2\, or
  anything preventing NMNAT2 delivery to axons\, kills axons. Gain-of-funct
 ion mutation of SARM1\, or its direct activation by at least one environme
 ntal toxin\, kills any neuronal compartment in which it becomes activated.
  Animal studies indicate wide relevance to neurological disorders\, and ge
 netic association now supports involvement in human polyneuropathies and A
 LS. Further function-altering variants of both human genes strongly sugges
 t a spectrum of intrinsic axon vulnerability that may influence other axon
 opathies too. This spectrum ranges from death in utero in rare cases of NM
 NAT2 biallelic null mutation\, through early onset disease or disease risk
  when there is partial loss-of-function of NMNAT2\, to modest protection f
 rom disease with SARM1 heterozygous loss-of-function. There are also some 
 dominant negative SARM1 alleles that could be strongly protective. This wo
 rk could lead towards personalized medicine for axonal disorders\, where i
 ndividuals at highest risk of activating programmed axon death can be iden
 tified from gene sequences\, and appropriate treatment and prevention meas
 ures applied. 
LOCATION:Zoom meeting
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