Nuclear Role of the Proteasome in Synaptic Plasticity

阐明突触改变用于长期记忆存储的机制对于 了解神经系统的正常和异常功能。多年来的调查显示 确定了新转录的基因需要新的基因转录和翻译 维持长期突触的可塑性和巩固长期记忆。在过去的几年中进行的研究 二十年来的研究表明，泛素-蛋白酶体途径(Upp)的蛋白分解在 突触可塑性和记忆。关于UPP的大部分工作都集中在它的传统功能上， 即底物蛋白质的降解。现在越来越清楚的是，蛋白酶体在 细胞如转录的调节。对非神经细胞类型进行的研究表明， 蛋白酶体与活跃转录基因的启动子结合并协助转录。其中一部分是 被称为19S调控复合体的蛋白酶体含有几种ATPase，其中Rpt1就是其中之一 在转录中发挥关键作用。我们将通过聚焦来研究蛋白酶体在转录中的作用。 在Rpt1上。我们将以海马区晚期长时程增强(L-LTP)为模型系统进行研究。 我们的初步数据显示，对L-LTP-1的反应，RPT1在海马片中移位到细胞核。 诱导性刺激。我们的结果还表明，Rpt1与脑源性神经营养因子的特定启动子结合。 脑源性神经营养因子基因。我们的第一个目标是将高通量测序方法与 Rpt1抗体染色质免疫沉淀鉴定Rpt1转录靶标。我们的第二个 目的是验证核Rpt1功能对转录和L-LTP至关重要的假说 维修。该项目将为阐明蛋白酶体的非常规作用奠定基础。 长期突触可塑性所需的转录，这将对理解 正常的长期记忆，以及在许多大脑疾病和紊乱中出现的记忆丧失。 此外，通过向本科生提供实践研究经验，该项目将 显著加强对未来生物医学科学家的培训。

Elucidating the mechanisms by which synapses are altered for long-term memory storage is crucial for understanding both normal and abnormal functions of the nervous system. Investigations over the years have established that new gene transcription and translation of the newly transcribed genes is required for maintenance of long-term synaptic plasticity and consolidation of long-term memory. Research during the last two decades has revealed that proteolysis by the ubiquitin-proteasome pathway (UPP) has an essential role in synaptic plasticity and memory. Much of the work on the UPP has been focused on its traditional function, namely, degradation of substrate proteins. It is now becoming clear that the proteasome has other roles in the cell such as regulation of transcription. Studies carried out on non-neuronal cell types have shown that the proteasome binds to promoters of actively transcribed genes and assists in transcription. A part of the proteasome called the 19S regulatory complex contains several ATPases among which Rpt1 has been shown to play a critical role in transcription. We will investigate the role of the proteasome in transcription by focusing on Rpt1. We will use hippocampal late phase long-term potentiation (L-LTP) as a model system for our studies. Our preliminary data show that Rpt1 translocates to the nucleus in hippocampal slices in response to L-LTP- inducing stimuli. Also, our results show that Rpt1 binds to specific promoters of the brain-derived neurotrophic factor (BDNF) gene. Our first aim is to use a high-throughput sequencing method in combination with chromatin immunoprecipitation with Rpt1 antibodies to identify the transcriptional targets of Rpt1. Our second aim is to test the hypothesis that the function of nuclear Rpt1 is critical for transcription and L-LTP maintenance. This project will lay the groundwork for elucidating the unconventional roles of the proteasome in transcription required for long-term synaptic plasticity which will have significant implications for understanding normal long-term memory as well as loss of memory seen in many diseases and disorders of the brain. Furthermore, by providing hands-on research experience to undergraduate students, this project will significantly enhance the training of future biomedical scientists.