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The stress-responsive gene GDPGP1/mcp-1 regulates neuronal glycogen metabolism and survival.

Authors
  • Schulz, Alexander1, 2
  • Sekine, Yuichi1, 3
  • Oyeyemi, Motunrayo J1, 2
  • Abrams, Alexander J1, 2
  • Basavaraju, Manasa1, 2
  • Han, Sung Min1, 2
  • Groth, Marco4
  • Morrison, Helen4
  • Strittmatter, Stephen M2, 3
  • Hammarlund, Marc1, 2
  • 1 Department of Genetics, Yale University, New Haven, CT.
  • 2 Department of Neuroscience, Yale University, New Haven, CT.
  • 3 Department of Neurology, Yale University, New Haven, CT.
  • 4 Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany. , (Germany)
Type
Published Article
Journal
The Journal of Cell Biology
Publisher
The Rockefeller University Press
Publication Date
Feb 03, 2020
Volume
219
Issue
2
Identifiers
DOI: 10.1083/jcb.201807127
PMID: 31968056
Source
Medline
Language
English
License
Unknown

Abstract

Maladaptive responses to stress might play a role in the sensitivity of neurons to stress. To identify novel cellular responses to stress, we performed transcriptional analysis in acutely stressed mouse neurons, followed by functional characterization in Caenorhabditis elegans. In both contexts, we found that the gene GDPGP1/mcp-1 is down-regulated by a variety of stresses. Functionally, the enzyme GDPGP1/mcp-1 protects against stress. Knockdown of GDPGP1 in mouse neurons leads to widespread neuronal cell death. Loss of mcp-1, the single homologue of GDPGP1 in C. elegans, leads to increased degeneration of GABA neurons as well as reduced survival of animals following environmental stress. Overexpression of mcp-1 in neurons enhances survival under hypoxia and protects against neurodegeneration in a tauopathy model. GDPGP1/mcp-1 regulates neuronal glycogen levels, indicating a key role for this metabolite in neuronal stress resistance. Together, our data indicate that down-regulation of GDPGP1/mcp-1 and consequent loss of neuronal glycogen is a maladaptive response that limits neuronal stress resistance and reduces survival. © 2019 Schulz et al.

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