Using human genetics to define a spectrum of axon vulnerability

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• Professor Michael Coleman from Department of Clinical Neurosciences, Cambridge Biomedical Campus
• Thursday 09 June 2022, 14:00-15:00
• Zoom meeting.

If you have a question about this talk, please contact Caroline Newnham.

Host - Cahir O’Kane

Studies from our group and others in model organisms, especially mice and Drosophila, have defined a molecular signalling pathway regulating axon survival after injury, termed programmed axon death. The same pathway can be activated by gene mutation, toxins and some viruses. At its core are the prodegenerative enzyme SARM1 and its upstream regulator, NMNAT2 , which is essential for axon survival. Both enzymes regulate levels of NAD and related metabolites. Loss-of-function mutation of NMNAT2 , or anything preventing NMNAT2 delivery to axons, kills axons. Gain-of-function mutation of SARM1 , or its direct activation by at least one environmental toxin, kills any neuronal compartment in which it becomes activated. Animal studies indicate wide relevance to neurological disorders, and genetic association now supports involvement in human polyneuropathies and ALS . Further function-altering variants of both human genes strongly suggest a spectrum of intrinsic axon vulnerability that may influence other axonopathies too. This spectrum ranges from death in utero in rare cases of NMNAT2 biallelic null mutation, through early onset disease or disease risk when there is partial loss-of-function of NMNAT2 , to modest protection from disease with SARM1 heterozygous loss-of-function. There are also some dominant negative SARM1 alleles that could be strongly protective. This work could lead towards personalized medicine for axonal disorders, where individuals at highest risk of activating programmed axon death can be identified from gene sequences, and appropriate treatment and prevention measures applied.

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