SARM1 signaling mechanisms in the injured nervous system
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)
- et al.
Axons matter: the promise of treating neurodegenerative disorders by targeting SARM1-mediated axonal degeneration
Trends Pharmacol Sci
(2020) - et al.
A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling
Gene Dev
(2005) - et al.
A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration
Cell Death Differ
(2015) - et al.
The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1
Nature
(2020) - et al.
A cell-permeant mimetic of NMN activates SARM1 to produce cyclic ADP-ribose and induce non-apoptotic cell death
Iscience
(2019) - et al.
Structure of the catalytic fragment of poly(AD-ribose) polymerase from chicken
Proc Natl Acad Sci
(1996) - et al.
Activation of autophagy during cell death requires the engulfment receptor Draper
Nature
(2010) - et al.
Dying neurons utilize innate immune signaling to prime glia for phagocytosis during development
Dev Cell
(2019) - et al.
Nmnat 1: a security guard of retinal ganglion cells (RGCs) in response to high glucose stress
Cell Physiol Biochem
(2016) - et al.
Wallerian degeneration is executed by an NMN-SARM1-dependent late Ca(2+) influx but only modestly influenced by mitochondria
Cell Rep
(2015)