TIR-1/SARM1 Inhibits Axon Regeneration

Abstract

An injured axon has two choices, regenerate or degenerate. In many neurons, the result is catastrophic axon degeneration and a failure to regenerate. To coerce the injured nervous system to regenerate, the molecular mechanisms that regulate both axon regeneration and degeneration need to be defined. We found that TIR-1/SARM1, a key regulator of axon degeneration, inhibits regeneration of injured motor axons. Loss of tir-1 function both reduces the frequency with which severed axon fragments degenerate and increases the frequency of axon regeneration. The increased regeneration in tir-1 mutants is not a secondary consequence of its effects on degeneration. Rather, TIR-1 carries out each of these opposing functions cell autonomously by regulating independent downstream genetic pathways. While promoting axon degeneration with the DLK-1 mitogen activated protein kinase (MAPK) signaling cascade, TIR-1 inhibits axon regeneration by activating the NSY-1/ASK1 MAPK signaling cascade. Our finding that TIR-1 regulates both axon regeneration and degeneration provides critical insight into how axons coordinately regulate the two key responses to injury, consequently informing approaches to manipulate the balance between these responses towards repair.

A phase transition enhances the catalytic activity of SARM1, an NAD+ glycohydrolase involved in neurodegeneration

“…The C. elegans GABA motor nervous system is composed of neurons that have cell bodies along the ventral nerve cord and extend axon commissures circumferentially around the body of the worm to the dorsal nerve cord. We visualized the GABA motor nervous system and TIR-1 using a transgenic strain that expresses cytosolic GFP and mScarlet::TIR-1b specifically in GABA motor neurons ( Figure 6D ; Julian and Byrne, 2020 ). Consistent with our cell culture studies, TIR-1 forms puncta in axons under basal conditions ( Figure 6D ).…”

SARM1-Dependent Axon Degeneration: Nucleotide Signaling, Neurodegenerative Disorders, Toxicity, and Therapeutic Opportunities

“…Axon blockage also occurs in bystander neurons, and this requires signaling to glia through Draper. Draper/Ask1 signaling downstream of dSARM plays a role in development, and in C. elegans this pathway appears to regulate regeneration of axons ( Brace and others 2022 ; Herrmann and others 2022 ; Julian and Byrne 2020 ). These diverging roles show multifaceted functions for SARM1 in neurons and will be an important future area of research.…”

Multifaceted roles of SARM1 in axon degeneration and signaling

“…In contrast to the degeneration of axons severed from the cell body, this response involves changes in gene expression, hence the cell body. A third cell autonomous injury response gated by Sarm1 was recently described in axotomized C. elegans motor axons, where Sarm1 inhibits the ability of injured axons to initiate regenerative axon growth ( Julian and Byrne, 2020 ). This response requires the ASK1 kinase and a p38-mediated arm of MAP Kinase signaling.…”

“…In addition to its most well-known for its role in promoting degeneration of the distal stump, SARM1 is also required for additional responses made by injured neurons. These include the JNK- and c-Jun-dependent release of cytokines ( Wang et al, 2018 ), the ability of neurons to regenerate in C. elegans ( Julian and Byrne, 2020 ), and in promoting death of oligodendrocytes in a glaucoma model ( Ko et al, 2020 ). SARM1 also functions within uninjured cells that participate in responses to injury, including uninjured “bystander” neurons (dark blue blue) ( Hsu et al, 2021 ), and immune cells that react to the damage (light blue) ( McLaughlin et al, 2019 ).…”