Pin1 in Synaptic Plasticity and Translation

突触可塑性和翻译中的 Pin1

基本信息

批准号：
7587857
负责人：
James S Malter
金额：
$ 37.13万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587857
关键词：
Ablation Alzheimer&apos s Disease Apoptosis Regulator Award Binding Proteins Biochemical Catabolism Catalytic Domain Cell Nucleus Cells Chemicals Cytoplasm Data Dendrites Dendritic Spines Drug Addiction Funding Genes Genetic Genetic Transcription Glutamate Receptor Glutamates Hippocampus (Brain)Human Isomerase Learning Location Long-Term Potentiation Maintenance Mediating Memory Messenger RNA Microtubule-Associated Proteins Mitotic Modification Molecular Mus Neurons Peptides Peptidylprolyl Isomerase Phosphotransferases Play Positioning Attribute Preparation Process Protein Biosynthesis Proteins Regulation Risk Role Scientist Signal Transduction Specificity Synapses Synaptic plasticity Training Translations Wages Western Blotting Work age related neurodegeneration chemical genetics memory acquisition neuronal cell body protein function protein kinase C zeta seryl-proline tau Proteins transcription factor

项目摘要

Consolidation of synaptic plasticity and memory requires biochemical alterations in the molecular composition of the synapse. The process of consolidation involves multiple processes including local translation of preexisting, dendritic mRNAs and results in changes in synaptic efficacy and storage of new memories that persist from days to years. While a few of the effectors of memory have been identified, relatively little is understood about how these molecules govern the induction of long-term forms of synaptic plasticity. We now show that Pin1, a cis-trans peptidyl-prolyl isomerase with specificity for Ser-Pro or Thr-Pro peptide bonds, plays a key role in synaptic plasticity. Pin1 is present in dendrites and spines and under basal conditions, suppresses dendritic protein synthesis. Glutamate signaling inactivates Pin1, leading to increased translation of many proteins including the plasticity related kinases PKMand PKC In the genetic absence of Pin1, hippocampal L-LTP is increased as are the levels of PKMand PKC. PKMand PKCactivity were necessary to maintain the suppression of Pin1 activity after glutamate signaling as well as dendritic translation. These data suggest glutamatergic signaling inhibits Pin1 which leads to the translation of PKM and PKC. Once produced, these kinases then support on-going dendritic translation partially by suppressing Pin1. As such our aims are to determine 1) the role of PKMin regulating Pin1 and 2) further characterize PKM function by identifying its downstream targets through chemical-genetics.

突触可塑性和记忆的巩固需要突触分子组成的生化改变。巩固过程涉及多个过程，包括预先存在的树突 mRNA 的局部翻译，并导致突触功效和新记忆存储的变化，并持续数天到数年。虽然已经确定了一些记忆效应因子，但人们对这些分子如何控制长期形式的突触可塑性的诱导知之甚少。肽酰脯氨酰异构酶对 Ser-Pro 或 Thr-Pro 肽键具有特异性，在突触可塑性中发挥关键作用，Pin1 存在于树突和棘中，在基础条件下，抑制树突蛋白合成，导致 Pin1 失活。许多蛋白质的翻译，包括可塑性相关激酶 PKM 和 PKC 在 Pin1 基因缺失的情况下，海马 L-LTP 增加，PKM 和 PKC 活性水平升高，是维持谷氨酸信号传导和树突翻译后 Pin1 活性抑制所必需的。这些数据表明谷氨酸信号传导受到抑制。 Pin1 导致 PKM 和 PKC 的翻译，一旦产生，这些激酶就会支持。部分通过抑制 Pin1 来进行持续的树突翻译，因此我们的目标是确定 1) PKM 在调节 Pin1 中的作用，以及 2) 通过化学遗传学识别其下游靶点来进一步表征 PKM 的功能。