Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases.
Publication Date
2021-10Journal Title
Neurotherapeutics
ISSN
1933-7213
Publisher
Springer Science and Business Media LLC
Volume
18
Issue
4
Pages
2200-2221
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Arthur-Farraj, P., & Coleman, M. P. (2021). Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases.. Neurotherapeutics, 18 (4), 2200-2221. https://doi.org/10.1007/s13311-021-01125-3
Description
Funder: john and lucille van geest foundation
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
Review, Wallerian degeneration, Programmed axon death, Repair Schwann cell, NMNAT2, SARM1, C-JUN, Regeneration, Neuregulin
Sponsorship
Wellcome Trust (UNS38871)
Biotechnology and Biological Sciences Research Council (BB/S009582/1)
Identifiers
s13311-021-01125-3, 1125
External DOI: https://doi.org/10.1007/s13311-021-01125-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333511
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.