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应激反应基因GDPGP1/mcp-1调节神经元糖原代谢和存活。

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

作者信息

Schulz Alexander, Sekine Yuichi, Oyeyemi Motunrayo J, Abrams Alexander J, Basavaraju Manasa, Han Sung Min, Groth Marco, Morrison Helen, Strittmatter Stephen M, Hammarlund Marc

机构信息

Department of Genetics, Yale University, New Haven, CT.

Department of Neuroscience, Yale University, New Haven, CT.

出版信息

J Cell Biol. 2020 Feb 3;219(2). doi: 10.1083/jcb.201807127.

DOI:10.1083/jcb.201807127
PMID:31968056
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7041677/
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.

摘要

对应激的适应不良反应可能在神经元对应激的敏感性中起作用。为了确定对应激的新型细胞反应，我们在急性应激的小鼠神经元中进行了转录分析，随后在秀丽隐杆线虫中进行了功能表征。在这两种情况下，我们发现基因GDPGP1/mcp-1在多种应激下被下调。在功能上，酶GDPGP1/mcp-1可抵御应激。敲低小鼠神经元中的GDPGP1会导致广泛的神经元细胞死亡。秀丽隐杆线虫中GDPGP1的单一同源物mcp-1缺失，会导致GABA能神经元的退化增加，以及环境应激后动物存活率降低。在神经元中过表达mcp-1可提高缺氧条件下的存活率，并在tau蛋白病模型中预防神经退行性变。GDPGP1/mcp-1调节神经元糖原水平，表明这种代谢物在神经元抗应激中起关键作用。总之，我们的数据表明，GDPGP1/mcp-1的下调以及随之而来的神经元糖原丧失是一种适应不良反应，会限制神经元的应激抵抗力并降低存活率。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/f355595a496b/JCB_201807127_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/664383ecf352/JCB_201807127_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/495c25d3bc0b/JCB_201807127_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/d0c9a19a150d/JCB_201807127_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/a21cae61bfd3/JCB_201807127_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/22b297b75d14/JCB_201807127_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/3b132b14f8eb/JCB_201807127_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/5ebd42695cae/JCB_201807127_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/6e8ada77a003/JCB_201807127_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/da6fd8f2a379/JCB_201807127_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/f355595a496b/JCB_201807127_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/664383ecf352/JCB_201807127_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/495c25d3bc0b/JCB_201807127_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/d0c9a19a150d/JCB_201807127_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/a21cae61bfd3/JCB_201807127_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/22b297b75d14/JCB_201807127_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/3b132b14f8eb/JCB_201807127_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/5ebd42695cae/JCB_201807127_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/6e8ada77a003/JCB_201807127_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/da6fd8f2a379/JCB_201807127_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b81/7041677/f355595a496b/JCB_201807127_Fig7.jpg

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