University of Dundee

"Molecular regulation of axon degeneration in injury and disease"

Event Date: 
Friday, September 8, 2017 - 13:00 to 14:00
Event Location: 
MSI Small Lecture Theatre
Dr Satpal Virdee
Event Speaker: 
Professor Michael Coleman
Cambridge Neuroscience, University of Cambridge
Event Type: 

Axons and synapses are lost early in a wide range of neurodegenerative disorders, including peripheral neuropathy, Alzheimer’s disease, multiple sclerosis, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, glaucoma, hereditary spastic paraplegia and traumatic brain injury. Axonal transport is impaired in many of these conditions and declines substantially during normal ageing.


The Slow Wallerian degeneration protein (WldS) is an aberrant protein that preserves axons when they are injured or when axonal transport is impaired. It arose in mice but when ectopically expressed in transgenic rats, flies and zebrafish, or in transfected human neurons, it exerts the same protective effect.


Structure-function studies of WldS show that its intrinsic NAD synthesizing (Nmnat) activity is critical for axon survival. Of the three normal mammalian Nmnat isoforms, only Nmnat2 has been confirmed to be in axons. Nmnat2 is essential for axon survival and has a short half-life, so axons require its constant replenishment by axonal transport. When delivery of Nmnat2 is prevented by nerve injury, or by knockdown or knockout of Nmnat2, axons degenerate or fail to grow.  WldS can rescue them by replacing the Nmnat enzyme activity and does so for a prolonged period as it has a much longer half-life.


Events both upstream and downstream of Nmnat2 are emerging in a wider pathway regulating axon survival. We find that Nmnat2 turnover is regulated by its palmitoylation-dependent targeting to axonal transport vesicles, followed by ubiquitination. Prevention of this vesicle targeting unexpectedly enhances the protective capacity of Nmnat2 to a level higher even than that of WldS, suggesting a cytosolic site of action. Downstream of Nmnat2, we identify a rise in the metabolic intermediate NMN as a key event. Inhibition of Nampt, the enzyme catalyzing NMN synthesis, preserves injured axons. Sarm1, a Toll-like receptor adapter required for Wallerian degeneration, appears to act in the same pathway at a downstream site. Sarm1 is necessary for axon degeneration after Nmnat2 knockdown but its deletion neither stabilizes Nmnat2 nor prevents the rise in NMN.


Thus, Nampt inhibition pharmacologically mimics the protective effect of WldS and Sarm1 represents another site for intervention on the same pathway. As further details of this pathway emerge, new targets should become evident for the prevention of axon loss in ‘dying back’ disorders. 



Gilley, J., Orsomando, G., Nascimento-Ferreira, I., Hsueh, Y-P., and Coleman, M.P. (2015) Absence of SARM1 rescues development and survival of NMNAT2-deficient axons.  Cell Reports. 10: 1974-81


*Di Stefano, M., *Nascimento-Ferreira, I., Orsomando, G., Mori, V., Brown, R., Janeckova, L., Gilley, J., Loreto, A., Vargas, M., Worrell, L.A., Tickle, J., Herd-Smith, A., Godzik, K., Patrick, J., Webster, J.R.M., Marangoni, M., Carpi, F., Pucciarelli, S., Meng, W., Sagasti, A., Ribchester, R.R., Magni, G. and *Coleman, M.P., and *Conforti, L. (2014). A rise in NAD precursor nicotinamide mononucleotide (NMN) promotes axon degeneration. Cell Death Diff. 22: 731-42


*Conforti, L., *Gilley, J., and Coleman, M.P. (2014). Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat. Rev. Neurosci. 15: 394-405.


Osterloh, J.M., Yang, J., Rooney, T.M., Fox, A.N., Adalbert, R., Powell, E.H., Sheehan, A.E., Avery, M.A., Hackett, R., Logan, M.A., MacDonald, J.M., Ziegenfuss, J.S., Milde, S., Hou, Y-J., Nathan, C., Ding, A., Brown, R.H. Jr., Conforti, L., Coleman, M.P., Züchner, S., Tessier-Lavigne, M. and Freeman, M.R. (2012). dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337: 481-4.


MRC Protein Phosphorylation and Ubiquitylation Seminar