RP9: Ubiquitylation-controlled Arc/Arg3.1 translation and protein turnover in synaptic plasticity and memory consolidation

突触可塑性和长期记忆的持久形式依赖于基因转录和蛋白质合成。一个具体的例子可以在Arc/Arg3.1的表达中看到，Arc/Arg3.1对于突触可塑性和记忆的巩固是必不可少的。在可塑性产生刺激时，Arc/Arg3.1 mRNA被诱导并靶向树突。在树突Zinki内，作为Arc/Arg3.1翻译的阻遏物的mRNA结合蛋白通过泛素/蛋白酶体系统降解。除了翻译抑制的活性依赖性缓解外，Arc/Arg3.1蛋白具有短的半衰期，表明Arc/Arg3.1通过蛋白质周转进行额外调节。我们将提出以下问题：i）树突状mRNA结合蛋白Zinki如何发挥Arc/Arg3.1 mRNA的翻译控制，ii）确定Zinki的活性依赖性泛素化和蛋白酶体降解如何有助于突触输入特异性，iii）定义控制Arc/Arg3.1蛋白周转的分子途径，以及iv）询问这些对AMPA受体运输的功能后果，内稳态可塑性和记忆

Enduring forms of synaptic plasticity and long-term memory are dependent on gene transcription and protein synthesis. A specific example can be seen in the expression of Arc/Arg3.1 which is essential for the consolidation of synaptic plasticity and memories. Upon plasticity-producing stimulation Arc/Arg3.1 mRNA is induced and targeted to dendrites. Within dendrites Zinki, an mRNA binding protein that acts as a repressor of Arc/Arg3.1 translation, becomes degraded via the ubiquitin/proteasome system. Besides activity-dependent relief of translational repression, Arc/Arg3.1 protein has a short halflife, suggesting additional regulation of Arc/Arg3.1 by protein turnover. We will ask the following questions: i) how translational control of Arc/Arg3.1 mRNA is exerted by the dendritic mRNA binding protein Zinki, ii) determine how activity-dependent ubiquitylation and proteasomal degradation of Zinki might contribute to synaptic input specificity, iii) define the molecular pathways that control Arc/Arg3.1 protein turnover and iv) ask what functional consequence these bear on AMPA receptor trafficking, homeostasis, plasticity, and memory.