MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2

Lauren J Walker; Daniel W Summers; Yo Sasaki; E J Brace; Jeffrey Milbrandt; Aaron DiAntonio

doi:10.7554/eLife.22540

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MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2

Journal article

Open access

Peer reviewed

MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2

Lauren J Walker, Daniel W Summers, Yo Sasaki, E J Brace, Jeffrey Milbrandt and Aaron DiAntonio

eLife, Vol.6, e22540

01/17/2017

DOI: 10.7554/eLife.22540

PMCID: PMC5241118

PMID: 28095293

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https://doi.org/10.7554/eLife.22540View

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Abstract

Injury-induced (Wallerian) axonal degeneration is regulated via the opposing actions of pro-degenerative factors such as SARM1 and a MAPK signal and pro-survival factors, the most important of which is the NAD biosynthetic enzyme NMNAT2 that inhibits activation of the SARM1 pathway. Here we investigate the mechanism by which MAPK signaling facilitates axonal degeneration. We show that MAPK signaling promotes the turnover of the axonal survival factor NMNAT2 in cultured mammalian neurons as well as the ortholog dNMNAT in motoneurons. The increased levels of NMNAT2 are required for the axonal protection caused by loss of MAPK signaling. Regulation of NMNAT2 by MAPK signaling does not require SARM1, and so cannot be downstream of SARM1. Hence, pro-degenerative MAPK signaling functions upstream of SARM1 by limiting the levels of the essential axonal survival factor NMNAT2 to promote injury-dependent SARM1 activation. These findings are consistent with a linear molecular pathway for the axonal degeneration program.

Signal Transduction

Mitogen-Activated Protein Kinase Kinases - metabolism

Animals

Nicotinamide-Nucleotide Adenylyltransferase - metabolism

Drosophila

Armadillo Domain Proteins - metabolism

Cells, Cultured

Nerve Degeneration - physiopathology

Cytoskeletal Proteins - metabolism

Mice

Details

Title: Subtitle: MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2
Creators: Lauren J Walker - Department of Developmental Biology, Washington University Medical School, Saint Louis, United States
Daniel W Summers - Department of Genetics, Washington University Medical School, Saint Louis, United States
Yo Sasaki - Department of Genetics, Washington University Medical School, Saint Louis, United States
E J Brace - Department of Developmental Biology, Washington University Medical School, Saint Louis, United States
Jeffrey Milbrandt - Hope Center for Neurological Disorders, Saint Louis, United States
Aaron DiAntonio - Hope Center for Neurological Disorders, Saint Louis, United States
Resource Type: Journal article
Publication Details: eLife, Vol.6, e22540
DOI: 10.7554/eLife.22540
PMID: 28095293
PMCID: PMC5241118
NLM abbreviation: Elife
ISSN: 2050-084X
eISSN: 2050-084X
Publisher: England
Grant note: R01 NS087632 / NINDS NIH HHS R01 NS065053 / NINDS NIH HHS
Language: English
Date published: 01/17/2017
Academic Unit: Iowa Neuroscience Institute; Biology
Record Identifier: 9984070120702771

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