A dual leucine kinase–dependent axon self-destruction program promotes Wallerian degeneration
Open accessAbstract
Axon degeneration underlies many common neurological disorders, but the signaling pathways that orchestrate axon degeneration are unknown. We found that dual leucine kinase (DLK) [corrected to add (DLK) abbreviation] promoted degeneration of severed axons in Drosophila and mice, and that its target, c-Jun N-terminal kinase, promoted degeneration locally in axons as they committed to degenerate. This pathway also promoted degeneration after chemotherapy exposure and may be a component of a general axon self-destruction program.
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At baseline, NLK is highly expressed in the CNS, and its expression is unregulated by oxidative and osmotic stress.
“At baseline, NLK is highly expressed in the CNS, and its expression is unregulated by oxidative and osmotic stress (52, 53), conditions associated with the cytosolic accumulation of TDP43 and other, predominantly nuclear, RNA binding proteins.”
From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [52]
The passages on axon degeneration discuss DLK and JNK, not NLK. Searches for NLK, Nemo-like kinase, CNS expression, and oxidative or osmotic stress found no passage in our copy addressing the attributed claim. (LLM, conf=0.76)
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Research works printed but not linked: 15
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Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
“…involved in ALS/FTLD-TDP disease pathogenesis, we initially investigated NLK expression in progranulin knockout ( GRN -KO) mature brain organoids (mbOrgs), an FTLD-TDP model neurons overexpressing dual leucine zipper kinase (DLK), a key regulator of axon degeneration and neuronal survival (52–54).”
- Authors
- Miller, B. R., Press, C., Daniels, R. W., Sasaki, Y., Milbrandt, J., & DiAntonio, A.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- DiAntonio, Aaron
- Venue
- Nature Neuroscience
- Published
- 2009-03-15
- Volume
- 12
- Issue
- 4
- Pages
- 387-389
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2696160
- OpenAlex
- W2029630756
- Cited by
- 301
- References
- 0
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 17 · 2023: 10 · 2022: 13 · 2021: 22 · 2020: 18 · 2019: 26 · 2018: 17 · 2017: 21 · 2016: 18 · 2015: 11 · 2014: 20 · 2013: 28 · 2012: 22
- FWCI
- 8.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG 13730, P 50 AG05681, P50AG005681, R01AG013730)
- National Institute on Drug Abuse (DA020812, R01DA020812)
- National Institute of Neurological Disorders and Stroke (R01NS040745, P30NS057105, NS040745)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Keywords
- axonal degeneration, Wallerian degeneration, DLK, c-Jun N-terminal kinase, JNK signaling, Drosophila, mouse model
- MeSH terms
- Animals, Anthracenes, Axons, Cells, Cultured, Disease Models, Animal, Drosophila, Embryo, Mammalian, Enzyme Inhibitors, Ganglia, Spinal, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Sciatic Nerve, Wallerian Degeneration, Olfactory Receptor Neurons, Axotomy, MAP Kinase Kinase Kinases, Animals, Genetically Modified, JNK Mitogen-Activated Protein Kinases, Green Fluorescent Proteins, Mice
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