Journal article
Nerve Growth Factor Signaling Tunes Axon Maintenance Protein Abundance and Kinetics of Wallerian Degeneration
Molecular biology of the cell, Vol.36(4), ar46
04/01/2025
DOI: 10.1091/mbc.E25-01-0005
PMCID: PMC12005098
PMID: 39969989
Abstract
Neurotrophic factors are critical for establishing functional connectivity in the nervous system and sustaining neuronal survival through adulthood. As the first neurotrophic factor purified, nerve growth factor (NGF) is extensively studied for its prolific role in axon outgrowth, pruning, and survival. Applying NGF to diseased neuronal tissue is an exciting therapeutic option and understanding how NGF regulates local axon susceptibility to pathological degeneration is critical for exploiting its full potential. Our study identifies surprising connections between NGF signaling and proteostasis of axon maintenance factors. NGF deprivation increases Nmnat2 and Stmn2 protein levels in axon segments with a corresponding delay in Wallerian degeneration. Conversely, acute NGF stimulation reduces local abundance of these axon maintenance factors and accelerates Wallerian degeneration. Pharmacological studies implicate phospholipase C as the key effector in TrkA activation, which drives degradation of palmitoylated Stmn2. While seemingly opposed to neuroprotective activities well-documented for NGF, downregulating Nmnat2 and Stmn2 favors axonal outgrowth over transient hyper-susceptibility to Sarm1-dependent degeneration. This new facet of NGF biology has important implications for axonal remodeling during development and sustained integrity through adulthood.
Details
- Title: Subtitle
- Nerve Growth Factor Signaling Tunes Axon Maintenance Protein Abundance and Kinetics of Wallerian Degeneration
- Creators
- Joseph A Danos - Department of BiologyMerve Addemir - Department of BiologyLily McGettigan - Department of BiologyDaniel W Summers - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular biology of the cell, Vol.36(4), ar46
- DOI
- 10.1091/mbc.E25-01-0005
- PMID
- 39969989
- PMCID
- PMC12005098
- NLM abbreviation
- Mol Biol Cell
- ISSN
- 1939-4586
- eISSN
- 1939-4586
- Publisher
- AMER SOC CELL BIOLOGY
- Grant note
- National Institutes of Health: RO1NS126191
ACKNOWLEDGMENTS Research described in this manuscript was supported by funds from the National Institutes of Health to D.W.S. (RO1NS126191) . We ap-preciate thoughtful comments from members of the Summers dur-ing preparation of this manuscript.
- Language
- English
- Electronic publication date
- 02/19/2025
- Date published
- 04/01/2025
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984792361702771
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