Elsevier

Current Opinion in Neurobiology

Volume 69, August 2021, Pages 247-255
Current Opinion in Neurobiology

SARM1 signaling mechanisms in the injured nervous system

https://doi.org/10.1016/j.conb.2021.05.004Get rights and content

Abstract

Axon degeneration is a prominent feature of the injured nervous system, occurs across neurological diseases, and drives functional loss in neural circuits. We have seen a paradigm shift in the last decade with the realization 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. Here, we review our current knowledge of SARM1 function in vivo and our evolving understanding of its complex architecture and 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 more complicated, and there remains much to learn about how SARM1 governs nervous system responses to injury or disease.

Introduction

Axon degeneration occurs after neural injury and is a common feature of several acute and chronic, sporadic, and familial neurological disorders including multiple sclerosis [1], spinal muscular atrophy [2], amyotrophic lateral sclerosis, Parkinson's disease, traumatic brain injury (TBI), stroke, and myelin disorders [3]. It also occurs in peripheral neuropathies associated with chemotherapeutic regimens and in diabetes and genetic peripheral neuropathies (e.g. Charcot-Marie-Tooth disease). Axonal degeneration drives the progressive loss of neurological function in patients suffering from neurodegenerative conditions [4, 5, 6], with functional loss in part resulting from the breakdown of circuit integrity. Despite its broad association with several diseases, we are only beginning to understand the molecular mechanisms that drive axon degeneration in any context. A comprehensive elucidation of molecules/pathways that drive axon degeneration and, ultimately, therapeutic blockade of these pathways to preserve axon integrity in patients are central goals for the field.

The characterization of the Wallerian degeneration (WD) pathway as the axon-intrinsic, injury-activated molecular pathway has reinvigorated an interest in targeting axon degeneration in human disease. Central to the pathway is mammalian sterile-alpha and TIR motif containing 1 (SARM1) (dSarm in Drosophila, Toll and Interleukin 1 receptor domain protein (TIR-1) in Caenorhabditis elegans), a primary regulator of axon auto-destruction [7••,8•,9•]. Significant progress has been made over the last decade in defining the phenotypic consequences of SARM1 loss, SARM1 enzymology and signaling, and how NAD+ metabolites regulate SARM1 activation. This review will discuss new roles for SARM1 in the injured nervous system, how new molecular knowledge about SARM1 enzymology and structure can be reconciled with in vivo function and highlight key questions for the future. The role of SARM1 in neurological diseases was recently reviewed [6] and will not be covered here.

Section snippets

How does Sarm1 signal in vivo?

Axotomy separates a distal axon stump from its cell body. After a latent phase, distal stumps undergo sudden and explosive fragmentation (WD). Two factors that likely drive WD are increases in axonal calcium [10] and depletion of NAD+/ATP [11]. In many experimental systems, axonal calcium levels increase dramatically immediately before degeneration, and blockade of calcium entry can significantly extend axon survival [12], but precise role(s) for calcium in driving axon degeneration remain

dSarm signals in two phases—early with MAPK and late with Axundead

Some clarity on the complex interaction between Sarm1 and MAPK signaling recently came from work in Drosophila [15••]. In the Drosophila L1 wing nerve, it is possible to injure a subset of neurons and then examine the responses of both distal severed axon stumps and intact neighboring neurons (termed ‘bystanders’), with single-cell/axon resolution. Within hours after injury of even a small number of axons, the transport of autophagosomes, lysosomes, and synaptic vesicles along axons is strongly

Insights into SARM1 activation from structural biology

Emerging data on the structure, enzymatic function, and regulation of SARM1 are also growing our understanding of this complex metabolic sensor and axon death executioner. As discussed previously, SARM1 is a structurally complex, multidomain protein with an auto-inhibitory ARM domain, tandem oligomerization SAM domains, and a catalytic TIR domain [8•,14,27]. The multidomain architecture of the full-length protein with flexible interdomain interactions has made elucidation of high-resolution

Reconciling current models with structural and enzymology data and in vivo biology?

It is not clear how SARM1 gets activated at each phase of signaling. In the context of axon degeneration, the substrates of both Nmnat (NMN) and Sarm1 (NAD+) have been proposed as regulators of SARM1. At least in vitro, NAD+ stabilizes the ARM domain to repress SARM1 NADase activity [32,33•], and NMN destabilizes the ARM domain to potentially promote it [28•,31••]. A simple model is that Nmnat turnover in severed axons increases NMN and decreases NAD+, and SARM1 is activated. This two-trigger

Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.R.F. is a co-founder of Nura Bio, Inc. S.S.S. is the Vice President of Biology at Nura Bio, Inc.

Acknowledgements

MRF is funded by NIH (R01 NS059991) and OHSU. We thanks Thomas Burdett for help making figures.

References (50)

  • T.J. Simkins et al.

    Chronic demyelination and axonal degeneration in multiple sclerosis: pathogenesis and therapeutic implications

    Curr Neurol Neurosci

    (2021)
  • L. Kong et al.

    Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA

    Sci Transl Med

    (2021)
  • M. Coleman

    Axon degeneration mechanisms: commonality amid diversity

    Nat Rev Neurosci

    (2005)
  • M.E. Shy et al.

    Axonal Charcot-Marie-Tooth disease

    Curr Opin Neurol

    (2011)
  • M.P. Coleman et al.

    Programmed axon degeneration: from mouse to mechanism to medicine

    Nat Rev Neurosci

    (2020)
  • J.M. Osterloh et al.

    dSarm/Sarm1 is required for activation of an injury-induced axon death pathway

    Science

    (2012)
  • J. Gerdts et al.

    Sarm1-mediated axon degeneration requires both SAM and TIR interactions

    J Neurosci: Off J Soc Neurosci

    (2013)
  • L.J. Neukomm et al.

    Axon death pathways converge on axundead to promote functional and structural axon disassembly

    Neuron

    (2017)
  • W.W. Schlaepfer et al.

    Effects of calcium ion concentration on the degeneration of amputated axons in tissue culture

    J Cell Biol

    (1973)
  • J. Wang et al.

    A local mechanism mediates NAD-dependent protection of axon degeneration

    J Cell Biol

    (2005)
  • E. George et al.

    Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels

    J Neurosci

    (1995)
  • M.E. Vargas et al.

    Live imaging of calcium dynamics during axon degeneration reveals two functionally distinct phases of calcium influx

    J Neurosci: Off J Soc Neurosci

    (2015)
  • J.-M. Hsu et al.

    Injury-induced inhibition of bystander neurons requires dSarm and signaling from glia

    Neuron

    (2021)
  • J. Yang et al.

    Pathological axonal death through a MAPK cascade that triggers a local energy deficit

    Cell

    (2015)
  • B.R. Miller et al.

    A dual leucine kinase–dependent axon self-destruction program promotes Wallerian degeneration

    Nat Neurosci

    (2009)
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