Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene
Abstract
Axons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/WldS mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD+ content, was increased fourfold in WldS tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.
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The protective effects in WldS mice are attributed to a chimeric gene Ube4b/NMNAT1, which encodes an in-frame fusion protein of the amino-terminal of UBE4B and the complete coding region of NMNAT1.
“The protective effects occurring in these mice are attributed to a chimeric gene Ube4b/NMNAT1, which encodes an in-frame fusion protein of the amino-terminal of ubiquitination factor E4B (UBE4B) and the complete coding region of NMNAT1 (83,84).”
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References 47 · Cited by 611
- Authors
- Mack, T. G. A., Reiner, M., Beirowski, B., Mi, W., Emanuelli, M., Wagner, D., Thomson, D., Gillingwater, T., Court, F., Conforti, L., Fernando, F. S., Tarlton, A., Andressen, C., Addicks, K., Magni, G., Ribchester, R. R., Perry, V. H., & Coleman, M. P.
- Affiliations
- University of Cologne (DE)
- University of Edinburgh (GB)
- Mario Negri Institute for Pharmacological Research (IT)
- University of Oxford (GB)
- University of Southampton (GB)
- Corresponding author
- Coleman, Michael P.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2001-11-19
- Volume
- 4
- Issue
- 12
- Pages
- 1199-1206
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2165565339
- Cited by
- 611
- References
- 47
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 7 · 2023: 14 · 2022: 35 · 2021: 24 · 2020: 38 · 2019: 25 · 2018: 25 · 2017: 26 · 2016: 23 · 2015: 26 · 2014: 27 · 2013: 38 · 2012: 37
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- ERA (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Wallerian degeneration, axonal injury, UBE4B, nicotinamide mononucleotide adenylyltransferase, axon protection, fusion genes, ubiquitination, NAD+ metabolism, pyridine nucleotides, neuromuscular junction, nuclear localization
- MeSH terms
- Action Potentials, Animals, Axons, Base Sequence, Cell Nucleus, Cell Survival, Fungal Proteins, Immunohistochemistry, Mice, Mutant Strains, Mice, Transgenic, Microscopy, Electron, Molecular Sequence Data, Motor Neurons, Mutation, Nerve Tissue Proteins, Nervous System, Synaptic Transmission, Neuromuscular Junction, Nicotinamide-Nucleotide Adenylyltransferase, Recombinant Fusion Proteins, Sciatic Nerve, Synaptic Vesicles, Wallerian Degeneration, Muscle, Skeletal, Trauma, Nervous System, Saccharomyces cerevisiae Proteins, Ubiquitin-Conjugating Enzymes, Mice
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