Klein Matthew E, Castillo Pablo E, Jordan Bryen A
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cell Rep. 2015 Mar 10;10(9):1459-1466. doi: 10.1016/j.celrep.2015.02.020. Epub 2015 Mar 5.
Dendritic protein homeostasis is crucial for most forms of long-term synaptic plasticity, and its dysregulation is linked to a wide range of brain disorders. Current models of metabotropic glutamate receptor mediated long-term depression (mGluR-LTD) suggest that rapid, local synthesis of key proteins is necessary for the induction and expression of LTD. Here, we find that mGluR-LTD can be induced in the absence of translation if the proteasome is concurrently inhibited. We report that enhanced proteasomal degradation during the expression of mGluR-LTD depletes dendritic proteins and inhibits subsequent inductions of LTD. Moreover, proteasome inhibition can rescue mGluR-LTD in mice null for the RNA binding protein Sam68, which we show here lack mGluR-dependent translation and LTD. Our study provides mechanistic insights for how changes in dendritic protein abundance regulate mGluR-LTD induction. We propose that Sam68-mediated translation helps to counterbalance degradation, ensuring that protein levels briefly remain above a permissive threshold during LTD induction.
树突状蛋白稳态对于大多数形式的长期突触可塑性至关重要，其失调与多种脑部疾病有关。当前代谢型谷氨酸受体介导的长期抑郁（mGluR-LTD）模型表明，关键蛋白的快速局部合成对于LTD的诱导和表达是必要的。在此，我们发现如果同时抑制蛋白酶体，则在没有翻译的情况下也可以诱导mGluR-LTD。我们报告说，在mGluR-LTD表达过程中增强的蛋白酶体降解会耗尽树突状蛋白并抑制随后的LTD诱导。此外，蛋白酶体抑制可以挽救RNA结合蛋白Sam68缺失的小鼠中的mGluR-LTD，我们在此表明这些小鼠缺乏mGluR依赖性翻译和LTD。我们的研究为树突状蛋白丰度的变化如何调节mGluR-LTD诱导提供了机制上的见解。我们提出，Sam68介导的翻译有助于抵消降解，确保在LTD诱导期间蛋白质水平短暂地保持在允许阈值以上。
