Nerve Growth Factor Signaling Tunes Axon Maintenance Protein Abundance and Kinetics of Wallerian Degeneration

Joseph A Danos; Merve Addemir; Lily McGettigan; Daniel W Summers

doi:10.1101/2024.12.31.630780

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Nerve Growth Factor Signaling Tunes Axon Maintenance Protein Abundance and Kinetics of Wallerian Degeneration

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Nerve Growth Factor Signaling Tunes Axon Maintenance Protein Abundance and Kinetics of Wallerian Degeneration

Joseph A Danos, Merve Addemir, Lily McGettigan and Daniel W Summers

bioRxiv

Cold Spring Harbor Laboratory

01/01/2025

DOI: 10.1101/2024.12.31.630780

PMCID: PMC11722262

PMID: 39803444

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https://doi.org/10.1101/2024.12.31.630780View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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 - University of Iowa
Merve Addemir - University of Iowa
Lily McGettigan - University of Iowa
Daniel W Summers - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2024.12.31.630780
PMID: 39803444
PMCID: PMC11722262
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Grant note: R01 NS126191 / NINDS NIH HHS
Language: English
Date posted: 01/01/2025
Academic Unit: Iowa Neuroscience Institute; Biology
Record Identifier: 9984774233502771

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