Pin1 in Synaptic Plasticity and Translation

突触可塑性和翻译中的 Pin1

• 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
• 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' 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

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.

突触的可塑性和记忆的巩固需要突触分子组成的生化改变。整合过程涉及多个过程，包括预先存在的树突状mRNAs的局部翻译，并导致突触效力的变化和新记忆的存储，从几天到几年。虽然已经确定了一些记忆的效应器，但对于这些分子如何管理长期形式的突触可塑性的诱导，人们了解的相对较少。PIN1是一种对Ser-Pro或Thr-Pro多肽键具有特异性的顺式-反式多肽-Pro异构酶，在突触可塑性中起着关键作用。Pin1存在于树突和棘中，在基础条件下，抑制树突状蛋白质的合成。谷氨酸信号使PIN1失活，导致许多蛋白质的翻译增加，包括可塑性相关的和。在PIN1基因缺失的情况下，海马L-LTP增加，PKM和PKC水平增加。蛋白激酶和蛋白激酶C活性是维持谷氨酸信号转导和树突翻译后PIN1活性抑制所必需的。这些数据表明，谷氨酸能信号抑制PIN1，而PIN1导致PKM和PKC的翻译。一旦产生，这些激酶就会部分地通过抑制Pin1来支持正在进行的树突翻译。因此，我们的目标是1)确定pKM在调节PIN1中的作用；2)通过化学遗传学确定其下游靶标，进一步研究pKM的功能。