c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy

Abstract

Charcot-Marie-Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot-Marie-Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot-Marie-Tooth disease type 1A. In line with our previous findings in humans with Charcot-Marie-Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun(-/-) mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot-Marie-Tooth disease type 1A: on the one hand they are the genetic source of the disease, on the other, they respond to it by mounting a c-Jun-dependent response that significantly reduces its impact. Because axonal death is a central feature of much nerve pathology it will be important to establish whether an axon-supportive Schwann cell response also takes place in other conditions. Amplification of this axon-supportive mechanism constitutes a novel target for clinical intervention that might be useful in Charcot-Marie-Tooth disease type 1A and other neuropathies that involve axon loss.

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

“…3,63,64 In normal nerve, both genes are normally expressed in nonmyelinating SCs, but both L1CAM and NGFR are expressed in myelinating SCs of human skin. 66 Using the CMTES-R score, we did not observe a correlation of PMP22 mRNA levels (or NGFR/L1CAM) with severity of neuropathy. It is notable that most of the SC injury genes were not elevated in CMT1A.…”

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

“…Furthermore, the CMT1A phenotype has previously been thought to recapitulate certain aspects of nerve injury, in which Schwann cells are reprogrammed to undergo demyelination and initiate a program involving macrophage recruitment, downregulation of myelin genes, and secretion of factors that ultimately support nerve regeneration. One of the critical regulators of Schwann cell responses to nerve injury is the c-Jun transcription factor (41), which is also induced at the protein level in both rodent models of CMT1A and also in Schwann cells of skin biopsies from human patients (40,42,43). While c-Jun was induced in C22 mice, the data obtained here allowed us to determine whether the broader profile of deregulated genes in C22 overlap with those found in nerve injury.…”

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

“…The present study focused on the controlled expression of the c-Jun gene to provide time-restricted neurotrophic support for nerve regeneration, whereas previous studies have also showed that c-Jun is associated with tumor formation in some systems (56), potentially suppresses myelin genes (57), and has been implicated in demyelinating neuropathies (58). It was reported that more than 1000 genes were regulated by c-Jun in SCs after nerve injury, including the up-regulation of GDNF, sonic hedgehog, oligodendrocyte transcription factor 1, inhibitor of DNA binding 2, SRY-box 2, and runt-related transcription factor 2 and the down-regulation of myelin protein zero, myelin basic protein, and peripheral myelin protein 22 (48,59).…”