A local mechanism mediates NAD-dependent protection of axon degeneration
Open accessAbstract
Axon degeneration occurs frequently in neurodegenerative diseases and peripheral neuropathies. Important insight into the mechanisms of axon degeneration arose from findings that the degeneration of transected axons is delayed in Wallerian degeneration slow (Wlds) mice with the overexpression of a fusion protein with the nicotinamide adenine dinucleotide (NAD) synthetic enzyme, nicotinamide mononucleotide adenylyltransferase (Nmnat1). Although both Wlds and Nmnat1 themselves are functional in preventing axon degeneration in neuronal cultures, the underlying mechanism for Nmnat1- and NAD-mediated axon protection remains largely unclear. We demonstrate that NAD levels decrease in degenerating axons and that preventing this axonal NAD decline efficiently protects axons from degeneration. In support of a local protective mechanism, we show that the degeneration of axonal segments that have been separated from their soma could be prevented by the exogenous application of NAD or its precursor nicotinamide. Furthermore, we provide evidence that such Nmnat1/NAD-mediated protection is primarily mediated by their effects on local bioenergetics. Together, our results suggest a novel molecular pathway for axon degeneration.
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In mammals, over-expressing NMNATs significantly delays Wallerian degeneration of peripheral nerves.
“In mammals, over-expressing NMNATs significantly delays Wallerian degeneration of peripheral nerves (28)(29)(30)(31)(32)(33).”
From CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy (2012) · cites this paper as [30]
Figure 2 in Results and discussion reports that overexpressing Nmnat1 significantly delayed Wallerian degeneration (P < 0.001). Materials and methods identifies the model as cultured rat dorsal root ganglion explants, not intact peripheral nerves. The paper tests Nmnat1 and a fusion protein containing it, rather than NMNATs generally. (LLM, conf=0.88)
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References 31 · Cited by 352
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- Authors
- Wang, J., Zhai, Q., Chen, Y., Lin, E., Gu, W., McBurney, M. W., & He, Z.
- Affiliations
- Harvard University (US)
- Columbia University (US)
- University of Ottawa (CA)
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2005-07-25
- Volume
- 170
- Issue
- 3
- Pages
- 349-355
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2171458
- OpenAlex
- W2168693839
- Cited by
- 352
- References
- 31
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 25 · 2021: 19 · 2020: 27 · 2019: 13 · 2018: 12 · 2017: 15 · 2016: 18 · 2015: 14 · 2014: 19 · 2013: 26 · 2012: 13
- FWCI
- 7.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- axonal degeneration, NMNAT1, nicotinamide mononucleotide adenylyltransferase, NAD+, nicotinamide, axon protection, neurodegenerative diseases, peripheral neuropathy
- MeSH terms
- Adenosine Triphosphate, Animals, Axons, Cells, Cultured, NAD, Nerve Tissue Proteins, Niacinamide, Nicotinamide-Nucleotide Adenylyltransferase, Recombinant Fusion Proteins, Wallerian Degeneration, Sirtuins, Mice, Rats, Sirtuin 1
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