Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

Abstract

Since Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell. We discuss how nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha TIR motif containing protein 1 (SARM1) are required for axon survival and degeneration, respectively, how transcription factor c-JUN is essential for the Schwann cell response to nerve injury and what each tells us about disease mechanisms and potential therapies. Human genetic association with NMNAT2 and SARM1 strongly suggests aberrant activation of programmed axon death in polyneuropathies and motor neuron disorders, respectively, and animal studies suggest wider involvement including in chemotherapy-induced and diabetic neuropathies. In repair Schwann cells, cJUN is aberrantly expressed in a wide variety of human acquired and inherited neuropathies. Animal models suggest it limits axon loss in both genetic and traumatic neuropathies, whereas in contrast, Schwann cell secreted Neuregulin-1 type 1 drives onion bulb pathology in CMT1A. Finally, we discuss opportunities for drug-based and gene therapies to prevent axon loss or manipulate the repair Schwann cell state to treat acquired and inherited neuropathies and neuronopathies.

Keywords: C-JUN; NMNAT2; Neuregulin; Programmed axon death; Regeneration; Repair Schwann cell; SARM1; Wallerian degeneration.

Fig. 1

Overview of the molecular mechanisms within the axon and the Schwann cell during Wallerian degeneration. Upon nerve transection, the axonal transport of NMNAT2 is interrupted, and NMNAT2 already present in axons is degraded in a PHR1- and proteasome-dependent manner. Conversion of NMN to NAD by NMNAT2 is halted so NMN builds up inside the axon. NMN binds the SARM1 octamer, causing a conformational change and its activation. SARM1 activity generates cyclic ADP-ribose (cADPR) from NAD but also other products from nicotinamide adenine dinucleotide phosphate (NADP) and other substrates, such as nicotinic acid adenine dinucleotide phosphate (NaADP) and 2′-phospho-cyclic ADP-ribose (cADPRP). It is incompletely understood how SARM1 activation leads to further downstream steps in the axonal degeneration pathway, such as calcium release, ROS generation, ATP decline and the role of the molecule Axundead. The timings of the activation of the molecular pathways involved in the Schwann cell injury response in relation to those that regulate the axon degeneration machinery have not been fully delineated. It is likely that the majority of the Schwann cell injury response occurs during or slightly after axon degeneration has been executed. During axon degeneration, placental growth factor (Plgf) is released from axons and activates VEGF receptors leading to constriction of actin filaments in the Schwann cell, which helps break up axon fragments. It is possible that mTORC1 activation contributes to this process. Within the nucleus, c-JUN upregulation mediates a substantial amount of the Schwann cell response to nerve injury, especially repair program gene expression, cell shape change forming repair Schwann cells, upregulation of myelinophagy to aid in myelin sheath removal and repression of the myelin program through inhibition of Krox-20 function. Other pathways that aid myelin clearance include calcineurin, MEK-ERK, Notch and P38 MAPKinase pathway activation, though their full mechanism is not completely understood. Furthermore, TAM receptor phagocytosis also contributes to myelin clearance. Within the nucleus, both OCT6 and HDAC1/2 repress c-JUN function and the polycomb repressive complex 2 (PRC2) represses a number of other repair program genes. Broken lines with question marks highlight a hypothetical association or an unknown quality. Created with BioRender.com

Fig. 2

Overview of the molecular mechanisms of Schwann cell remyelination. Schwann cell remyelination is promoted by axonal signals centred around NRG1 type III and basal lamina signalling via the g-protein coupled receptor, GPR126, similar to myelination during development. One distinct molecular difference from development is that Schwann cell derived soluble NRG1 type I also contributes to remyelination. Certainly macroscopically, remyelination leads to thinner myelin sheaths and shorter internodal distances compared to developmental myelination. C-JUN is an inhibitor of remyelination and OGT, through direct O-GlcNAcylation, represses c-JUN function to allow remyelination to proceed. YAP/TAZ is required for remyelination, in addition to other important regulators of myelination, such as CTCF, ZEB2, HDAC1/2 and HDAC3. SLI = Schmidt-Lanterman incisure. Broken lines with question marks highlight a hypothetical association or an unknown quality. Created with BioRender.com