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Study of PAK3 in epilepsy-associated defects in synaptic plasticity

PAK3在癫痫相关突触可塑性缺陷中的研究

基本信息

批准号：
10046413
负责人：
Nien-Pei Tsai
金额：
$ 14.55万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046413
关键词：
Actin-Binding Protein Actins Address Affect Area Biological Assay Brain CDKN1A gene Chemosensitization Cognition Data Defect Development Disease Dissociation Epilepsy Foundations Genes Hippocampus (Brain)Impaired cognition Impairment In Vitro Intention Knowledge Lead Mediating Memory Memory impairment Missense Mutation Molecular Mutation Names Neurons Pathologic Patients Phosphorylation Phosphotransferases Pilot Projects Protein Isoforms Protein Kinase Proteins Proteomics Quality of life Recurrence Regulation Role Seizures Signal Transduction Synapses Synaptic plasticity Testing Ubiquitination United States Validation Work base cofilin comorbidity conditional knockout memory consolidation memory retrieval mouse model nerve stem cell novel optogenetics polymerization therapeutic effectiveness ubiquitin-protein ligase upstream kinase

项目摘要

PROJECT SUMMARY/ABSTRACT Epilepsy affects more than 3 million people in the United States. In addition to unprovoked seizures, cognitive decline and memory impairment are common comorbidities associated with epilepsy, but our knowledge in this area is limited. Our preliminary work suggests that an epilepsy associated ubiquitin E3 ligase Nedd4-2 mediates actin polymerization through promoting phosphorylation of an actin binding protein cofilin during the induction of long-term synaptic potentiation (LTP). LTP describes long‐lasting increments of synaptic efficiency and is crucial for cognition and memory formation. In an effort to identify ubiquitination substrates of Nedd4-2 responsible for cofilin phosphorylation, we identified PAK3, an IDG-eligible understudied kinase, as a potential substrate of Nedd4-2 that contributes to cofilin phosphorylation during LTP. This pilot project is formulated to test our hypothesis that induction of LTP de-represses Nedd4-2 to stabilize PAK3 and subsequently induce cofilin phosphorylation and actin polymerization. In Aim 1, we will determine how PAK3 is ubiquitinated by Nedd4-2 and how this ubiquitination is disrupted by epilepsy associated mutations in Nedd4-2. We will also determine whether induction of LTP de-represses Nedd4-2 to allow PAK3 stabilization during LTP. In Aim 2, we will employ a recently developed optogenetic approach to rapidly stabilize PAK3 in Nedd4-2 conditional knockout (cKO) neurons during the induction of LTP, with the intention to restore cofilin phosphorylation and actin polymerization, and ultimately to restore LTP. We expect our project to further our knowledge of an IDG-eligible protein PAK3 in synaptic plasticity and help explain cognitive decline in epilepsy.

项目总结/摘要在美国，癫痫影响着300多万人。除了无缘无故的癫痫发作认知能力下降和记忆障碍是与癫痫相关的常见合并症，但我们的这方面的知识有限。我们的初步工作表明，癫痫相关的泛素E3 连接酶Nedd 4 -2通过促进肌动蛋白结合蛋白磷酸化介导肌动蛋白聚合 Cofilin在长时程突触增强（LTP）诱导过程中的作用。LTP描述了长期持续的突触的效率，是至关重要的认知和记忆的形成。为了确定泛素化 Nedd 4 -2负责cofilin磷酸化的底物，我们鉴定了PAK 3，一个IDG合格的未充分研究的激酶，作为Nedd 4 -2的潜在底物，在LTP期间促进cofilin磷酸化。这一试点该项目是为了验证我们的假设，即诱导LTP去抑制Nedd 4 -2以稳定PAK 3，随后诱导cofilin磷酸化和肌动蛋白聚合。在目标1中，我们将确定PAK 3是如何泛素化的Nedd 4 -2和这种泛素化是如何破坏癫痫相关的突变Nedd 4 -2。我们还将确定LTP的诱导是否去抑制Nedd 4 -2以允许PAK 3在LTP期间稳定。在目标2中，我们将采用最近开发的光遗传学方法来快速稳定Nedd 4 -2中的PAK 3 条件性敲除（cKO）神经元在诱导LTP，目的是恢复cofilin 磷酸化和肌动蛋白聚合，并最终恢复LTP。我们希望我们的项目能进一步促进我们的 IDG合格蛋白PAK 3在突触可塑性方面的知识，并有助于解释癫痫的认知下降。