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.

中文翻译：

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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

对压力的适应不良反应可能在神经元对压力的敏感性中发挥作用。为了确定新的细胞对应激的反应，我们对急性应激的小鼠神经元进行了转录分析，然后对秀丽隐杆线虫进行了功能表征。在这两种情况下，我们发现基因 GDPGP1/mcp-1 因各种应激而下调。从功能上来说，GDPGP1/mcp-1 酶可以抵御压力。小鼠神经元中 GDPGP1 的敲低会导致广泛的神经元细胞死亡。线虫中 GDPGP1 的单一同源物 mcp-1 的缺失会导致 GABA 神经元退化加剧，并导致环境应激后动物的存活率降低。mcp-1 在神经元中的过度表达可增强缺氧条件下的存活率，并防止 tau 蛋白病模型中的神经变性。GDPGP1/mcp-1 调节神经元糖原水平，表明该代谢物在神经元应激抵抗中发挥关键作用。总之，我们的数据表明 GDPGP1/mcp-1 的下调和随之而来的神经元糖原的损失是一种适应不良反应，限制了神经元的应激抵抗力并降低了生存率。