Axon degeneration is a common hallmark of neuropathies, traumatic injury, and multiple neurodegenerative disorders. The molecular mechanism of axon degeneration has been primarily elucidated through the study of Wallerian axon destruction pathway. Wallerian degeneration, first described by the British neurophysiologist Augustus Waller in 1849 (1), refers to rapid axonal fragmentation after a long period of relative latency due to a genetically encoded self-destruction program that is activated distal to the point of the axon cut site (2–4). This is the most extreme and typical manifestation of axon degeneration. Over the past decades, great progress has been made in the understanding of this active process. The coordinated activity of both the pro-survival factors and the pro-degeneration factors, exemplified by nicotinamide mononucleotide adenyltransferase 2 (NMNAT2) and sterile-α and toll/interleukin 1 receptor motif containing protein 1 (SARM1), limits degeneration signaling in an “off” state in healthy axons. After axotomy, NMNAT2 is rapidly consumed in the axon segment distal to the injury site due to the interruption of axon transport and the degradation (5, 6), resulting in the hindrance of nicotinamide adenine dinucleotide (NAD+) synthesis. The disruption of NAD+ synthesis will increase the amount of nicotinamide mononucleotide (NMN), the precursor of NAD+, in the axon. The raised ratio of NMN and NAD+ (7) activates SARM1, which further consumes NAD+ to switch into the irreversible stage accompanied by adenosine triphosphate (ATP) depletion, neurofilament hydrolysis, and axon fragmentation (8).
SARM1 is the defining molecule of axon destruction. Activation of SARM1 triggers metabolic catastrophe and axon destruction, whereas genetic deletion protects axons from various injury (9). As the central executioner of axon degeneration, SARM1 is evolutionarily highly conserved, having homologues in mouse, Drosophila, zebrafish, Caenorhabditis elegans, amphioxus, and horseshoe crab (10–13). These homologues share a common domain architecture constituted of autoinhibitory N-terminal armadillo motifs (ARM), tandem sterile α motif (SAM) domains that mediate constitutive homomultimerization, and a C-terminal toll/interleukin 1 receptor (TIR) domain. The N-terminal SAM-TIR domain has NAD+ cleaving activity, and the activation induces axonal NAD+ depletion that is followed by ATP loss. So far, although we have a preliminary understanding of these domains, the function of SARM1 and its regulatory mechanisms still needs to be further studied. It is currently believed that elucidating the exact subcellular localization of SARM1 will offer insights into its functional role. Even though it remains to be defined, mitochondrial localization has been proposed. The N-terminal 27 amino acids of SARM1 are hydrophobic polybasic and have the capacity to fold into an α-helix that is required for association with the mitochondrial outer membrane. It serves as a mitochondria-targeting sequence, associating SARM1 to the mitochondria (14).
SARM1 and mitochondria are intimately connected. In addition to structural biological evidence that SARM1 has a mitochondrial import sequence, the two also have a metabolic connection. ATP produced in mitochondria provides energy for NAD+ synthesis (15), and NAD+ plays an important role in both oxidative phosphorylation and glycolysis (16, 17). NAD+ metabolic disorder is a necessary and sufficient condition for the activation of SARM1. The activated SARM1 with the NAD+ cleavage site exposed, consumes NAD+, accelerates energy exhaustion and initiates axon fragmentation. Indeed, ATP depletion is a defining indicator of the transition from the latent period to the irreversible period of Wallerian degeneration (8, 9). However, previous studies have shown that Wallerian degeneration is only modestly influenced by mitochondria (18). The biological significance of SARM1 mitochondrial localization has yet to be further explored.
To identify conditions that would benefit from blocking SARM1 dependent Wallerian axon destruction pathway, peripheral neuropathies are re-examined. Here, we want to explore whether the SARM1 dependent axon degeneration mechanism is involved in peripheral nerve damage in ACR poisoning? Further, if SARM1 is activated in this progress, are there any potential regulatory mechanisms?
As the vinyl monomer for the production of polyacrylamide, ACR is widely utilized in a variety of industrial settings and laboratories (19). In addition to occupational exposure, ACR in food, drinking water, coffee, and cigarette smoke has a potential hazard to the general population (20–23). In June 2002, a risk assessment of ACR in food was conducted in the joint Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) consultation. In reports of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the potential adverse neurological effects were noted among individuals with high dietary exposure to ACR. Chronic ACR intoxication induces peripheral neuropathy in people (24–27) and animals (28, 29), which are characterized by progressive axon degeneration of the distal ends of the longest and the largest nerve fibres. As exposure continues, progressive retrograde destruction of these distal axon regions ensues with preservation of more proximal segments resulting symptoms, that is, ataxia, skeletal muscle weakness and numbness of the hands and feet. The specific spatiotemporal pattern of axon damage is similar to the profile of Wallerian degeneration after axotomy (30–34) and is named as Wallerian-like degeneration. Studying the changes of SARM1 in such a slowly progressing and moderate axon destruction process will contribute to enhancing the understanding of Wallerian degeneration and explore its potential regulatory mechanism.