c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy
Open accessAbstract
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.
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In CMT1A, elevated Schwann cell autophagy is associated with higher levels of JUN/c-Jun.
“and associated with higher levels of JUN/c-Jun,”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [467]
Higher JUN/c-Jun in CMT1A may be part of a compensatory, neuroprotective response to the pathogenic effects of the PMP22 duplication.
“which may be part of a compensatory, neuroprotective response to the pathogenic effects of the PMP22 duplication [467–469].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [467]
In Charcot-Marie-Tooth type 1A caused by duplication of PMP22, Schwann cell autophagy is aberrantly elevated.
“in Charcot-Marie-Tooth (CMT) type 1A caused by duplication of PMP22 (peripheral myelin protein 22), Schwann cell autophagy is aberrantly elevated”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [467]
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“Schwann cells Activates [465] Activates [467,468] FIG4 [13] MIR195 [14,15]”
Background
- Authors
- Hantke, J., Carty, L., Wagstaff, L. J., Turmaine, M., Wilton, D. K., Quintes, S., Koltzenburg, M., Baas, F., Mirsky, R., & Jessen, K. R.
- Affiliations
- University College London (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Amsterdam UMC Location University of Amsterdam (NL)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-09-12
- Volume
- 137
- Issue
- 11
- Pages
- 2922-2937
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4208468
- OpenAlex
- W1971830677
- Cited by
- 76
- References
- 40
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 4 · 2023: 10 · 2022: 10 · 2021: 7 · 2020: 8 · 2019: 4 · 2018: 6 · 2017: 10 · 2016: 3 · 2015: 1 · 2014: 1
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Wellcome Trust (074665, 091119)
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- c-Jun, Schwann cells, Charcot-Marie-Tooth disease type 1A, axon survival, demyelinating neuropathy, F-wave, peripheral nerve injury, neuroprotection
- MeSH terms
- Animals, Axons, Behavior, Animal, Charcot-Marie-Tooth Disease, Demyelinating Diseases, Disease Models, Animal, Mice, Inbred C3H, Motor Neurons, Schwann Cells, Proto-Oncogene Proteins c-jun, Mice, Knockout, Mice
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