DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration

Daniel W Summers; Erin Frey; Lauren J Walker; Jeffrey Milbrandt; Aaron DiAntonio

doi:10.1007/s12035-019-01796-2

Back

DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration

Journal article

Peer reviewed

DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration

Daniel W Summers, Erin Frey, Lauren J Walker, Jeffrey Milbrandt and Aaron DiAntonio

Molecular neurobiology, Vol.57(2), pp.1146-1158

02/2020

DOI: 10.1007/s12035-019-01796-2

PMCID: PMC7035184

PMID: 31696428

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/7035184View

Open Access

Abstract

Axon degeneration is a prominent component of many neurological disorders. Identifying cellular pathways that contribute to axon vulnerability may identify new therapeutic strategies for maintenance of neural circuits. Dual leucine zipper kinase (DLK) is an axonal stress response MAP3K that is chronically activated in several neurodegenerative diseases. Activated DLK transmits an axon injury signal to the neuronal cell body to provoke transcriptional adaptations. However, the consequence of enhanced DLK signaling to axon vulnerability is unknown. We find that stimulating DLK activity predisposes axons to SARM1-dependent degeneration. Activating DLK reduces levels of the axon survival factors NMNAT2 and SCG10, accelerating their loss from severed axons. Moreover, mitochondrial dysfunction independently decreases the levels of NMNAT2 and SCG10 in axons, and in conjunction with DLK activation, leads to a dramatic loss of axonal NMNAT2 and SCG10 and evokes spontaneous axon degeneration. Hence, enhanced DLK activity reduces axon survival factor abundance and renders axons more susceptible to trauma and metabolic insult.

Animals

Nicotinamide-Nucleotide Adenylyltransferase - metabolism

Armadillo Domain Proteins - metabolism

Axons - metabolism

Cytoskeletal Proteins - metabolism

Mice

Mitochondria - metabolism

Neurons - metabolism

Cell Survival - physiology

Nerve Degeneration - metabolism

Nerve Degeneration - pathology

Details

Title: Subtitle: DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration
Creators: Daniel W Summers - Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
Erin Frey - Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
Lauren J Walker - Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
Jeffrey Milbrandt - Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO, 63110, USA. jmilbrandt@wustl.edu
Aaron DiAntonio - Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO, 63110, USA. diantonio@wustl.edu
Resource Type: Journal article
Publication Details: Molecular neurobiology, Vol.57(2), pp.1146-1158
DOI: 10.1007/s12035-019-01796-2
PMID: 31696428
PMCID: PMC7035184
NLM abbreviation: Mol Neurobiol
ISSN: 0893-7648
eISSN: 1559-1182
Publisher: United States
Grant note: NS087632 / NINDS NIH HHS 344513 / Muscular Dystrophy Association R01 CA219866 / NCI NIH HHS R01 NS087632 / NINDS NIH HHS RF1 AG013730 / NIA NIH HHS R01 AG013730 / NIA NIH HHS R01 CA218263 / NCI NIH HHS AG013730 / NIA NIH HHS NS65053 / NINDS NIH HHS R01 NS065053 / NINDS NIH HHS
Language: English
Date published: 02/2020
Academic Unit: Iowa Neuroscience Institute; Biology
Record Identifier: 9984070895302771

Metrics

32 Record Views

59 Times Cited - Web of Science