You are here

SARM1 Signaling In the Injured Nervous System

Who Should Attend: 
Event Flyer: 
PDF icon freeman_5-9-23.pdf



Axon degeneration is a prominent feature of the injured nervous system, occurs across neurological diseases, and drives functional loss in neural circuits. We discovered that injured axons are capable of actively driving their own destruction through the sterile-alpha and TIR motif containing 1 (SARM1) protein. Early studies of Wallerian degeneration highlighted a central role for NAD+ metabolites in axon survival, and this association has grown even stronger in recent years with a deeper understanding of SARM1 biology. This seminar will discuss our current knowledge of SARM1 function in vivo, and our evolving understanding of its complex architecture and potential regulation by injury-dependent changes in the local metabolic environment. The field is converging on a model whereby SARM1 acts as a sensor for metabolic changes that occur after injury, and then drives catastrophic NAD+ loss to promote degeneration. However, a number of observations suggest that SARM1 biology is much more complicated, and there remains much to learn about how SARM1 governs nervous system responses to injury or disease.

Nmnat2/NAD+ depletion model for axon degeneration

Nmnat2 is a survival factor transported down axons from the cell body that generates NAD+ from NMN.  After axotomy, the labile Nmnat2 molecule is depleted from distal severed axons, NAD+ drops, NMN rises, and Sarm1 is activated.  In mammalian neurons MAPK signaling (based on MKK4/7 phosphorylation) in axons peaks early, NAD+ drops hours later, and axon fragmentation begins.  Time reflects events in DRG primary cultures, in vivo times are much longer.


Shilpa Sambashivan, Marc R Freeman
SARM1 signaling mechanisms in the injured nervous system
Curr Opin Neurobiol . 2021 Aug;69:247-255. doi: 10.1016/j.conb.2021.05.004. Epub 2021 Jun 25.
Jiun-Min Hsu, Yunsik Kang, Megan M Corty, Danielle Mathieson, Owen M Peters, Marc R Freeman
Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia
Neuron . 2021 Feb 3;109(3):473-487.e5. doi: 10.1016/j.neuron.2020.11.012. Epub 2020 Dec 8.
Lukas J Neukomm, Thomas C Burdett, Andrew M Seeds, Stefanie Hampel, Jaeda C Coutinho-Budd, Jonathan E Farley, Jack Wong, Yonca B Karadeniz, Jeannette M Osterloh, Amy E Sheehan, Marc R Freeman
Axon Death Pathways Converge on Axundead to Promote Functional and Structural Axon Disassembly
Neuron . 2017 Jul 5;95(1):78-91.e5. doi: 10.1016/j.neuron.2017.06.031.


Tuesday, May 9, 2023 - 12:30pm


Zoom Meeting

More Information

Darlene White