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.

Age-Dependent Decline of NAD+—Universal Truth or Confounded Consensus?

“…CD38 is an NADase enzyme involved in cell adhesion, signal transduction and calcium signaling and plays a role in many cellular processes associated with aging and age-related chronic diseases [ 24 ] such as obesity [ 25 , 26 ], metabolic syndrome [ 27 ] and cancer [ 28 , 29 ]. Finally, SARM1 has pro-neurodegenerative properties, and while its function is not fully understood, it likely involves calcium mobilization through the generation of cyclic ADP-ribose (cADPR) [ 30 , 31 , 32 ].…”

C698R Lrsam1 knock-in mouse model for CMT2P

“…While the electrophysiological phenotype is subtle, it could contribute to the slowly progressive polyneuropathy in patients with CMT2P. As every person is exposed to many nerve injuries during their lifetime, we speculate that an accumulation of impaired nerve recoveries may eventually contribute to the polyneuropathy of CMT2P [16][17][18] .…”

The Role of c-Jun and Autocrine Signaling Loops in the Control of Repair Schwann Cells and Regeneration

“…The Schwann cell injury response is more radical and better characterized in myelin cells than in Remak cells ( Figures 2 – 4 ; reviewed in Chen et al, 2007 ; Glenn and Talbot, 2013 ; Jessen et al, 2015 ; Jessen and Mirsky, 2016 , 2019b ; Jessen and Arthur-Farraj, 2019 ; Zigmond and Echevarria, 2019 ; Kolter et al, 2020 ; Nocera and Jacob, 2020 ; Arthur-Farraj and Coleman, 2021 ; Min et al, 2021 ). This reprogramming event involves three types of change: (i) Up-regulation of repair phenotypes.…”