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Protein phosphatase 1 isoforms, human de novo mutations and synaptic functions

蛋白磷酸酶 1 亚型、人类从头突变和突触功能

基本信息

批准号：
10659549
负责人：
HOUHUI XIA
金额：
$ 57.19万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659549
关键词：
Biological Models C-terminal Catalytic Domain Cognition Cognitive deficits Compensation Complement Dendritic Spines Disease F-Actin Genes Goals Health Hippocampus Holoenzymes Human Impairment Intellectual functioning disability Knock-out Knockout Mice Knowledge Long-Term Potentiation Mammalian Cell Mediating Memory Molecular Morphogenesis Mus Muscle relaxation phase Myosin Regulatory Light Chains Neurabin Neurodegenerative Disorders Neurons Nonmuscle Myosin Type IIB Patients Phosphorylation Play Polymers Process Protein Dephosphorylation Protein Isoforms Protein phosphatase Reagent Role Scaffolding Protein Serine Serine/Threonine Phosphorylation Signal Transduction Societies Structure Synapses Synaptic Transmission Synaptic plasticity Terminator Codon Testing Therapeutic Therapeutic Intervention Vertebral column Work cell motility conditional knockout de novo mutation density developmental disease in vivo insight knock-down loss of function mouse model mutant myosin phosphatase neuropsychiatric disorder new therapeutic target non-muscle myosin polymerization prevent severe intellectual disability small hairpin RNA spatial memory synaptic function synaptic inhibition

项目摘要

Reversible phosphorylation is a critical regulatory mechanism for spine morphogenesis, synaptic transmission, long-term potentiation (LTP) and memory formation. Protein phosphatase 1 (PP1) contributes to almost half of the serine/threonine phosphorylation in the mammalian cells, however, the role of three different PP1 isoforms (PP1α, β, γ) in these processes is ill defined. PP1β is not believed to play a role in CNS function. On the other hand, whether PP1α and PP1γ play a role in synaptic functions have never been determined directly. By using conditional knockout mouse models, we found that PP1β inhibits synaptic transmission and spine maturation while promotes LTP induction and memory formation. On the other hand, we found that PP1γ increases synaptic transmission, with PP1α compensating PP1γ. The overarching hypothesis of this application is that myosin phosphatase targeting 1 (MYPT1) and neurabin (Nrb) mediate the distinct effects of PP1β and PP1γ/α on synaptic function, respectively. In detail, we will test our hypothesis in Aim 1 that PP1β-MYPT1 holoenzyme inhibits non-muscle myosin IIB-mediated F-actin contraction in inhibiting spine maturation and synaptic transmission. We will determine in Aim 2 that PP1γ, in combination with PP1α, promotes spine maturation, synaptic transmission by interaction with Nrb, a major synaptic scaffolding protein. We will also test our prediction that PP1γ/α achieves these via dephosphorylating Nrb at Ser200. In Aim 3 we will test our prediction that PP1β inhibits LTD induction, promotes LTP induction and memory formation while PP1γ/α plays an opposite role. We will determine the structure-synaptic function relationship in the roles of PP1β in synaptic transmission and plasticity, with an emphasis on PP1β C-termini in which one of the human PP1β de novo mutations resides. These studies will provide signaling mechanisms of, and structure determinants on, PP1 isoforms in regulating their distinct roles on synaptic functions.

可逆性磷酸化是脊髓形态发生、突触形成和突触后神经元凋亡的重要调控机制。长时程增强（LTP）和记忆形成。蛋白磷酸酶1（PP 1）有助于几乎一半的丝氨酸/苏氨酸磷酸化在哺乳动物细胞中，然而，三种不同的作用， PP 1亚型（PP 1 α、β、γ）在这些过程中的作用尚不清楚。 PP 1 β被认为在CNS功能中不起作用。另一方面，PP 1 α和PP 1 γ是否起作用，在突触功能中的作用从未被直接确定。通过使用条件性基因敲除小鼠模型，发现PP 1 β抑制突触传递和脊髓成熟，同时促进LTP诱导和记忆阵另一方面，我们发现，PP 1 γ增加突触传递，而PP 1 α补偿 PP1γ。本申请的首要假设是肌球蛋白磷酸酶靶向1（MYPT 1）和神经肽 (Nrb)分别介导了PP 1 β和PP 1 γ/α对突触功能的不同作用。具体来说，我们将测试我们在目的1中假设PP 1 β-MYPT 1全酶抑制非肌肉肌球蛋白IIB介导的F-肌动蛋白收缩抑制脊柱成熟和突触传递。我们将在目标2中确定PP 1 γ，与PP 1 α结合，促进棘成熟，通过与Nrb相互作用促进突触传递，突触支架蛋白我们还将验证我们的预测，即PP 1 γ/α通过去磷酸化 NRB在Ser 200。在目标3中，我们将测试我们的预测，即PP 1 β抑制LTD诱导，促进LTP诱导，而PP 1 γ/α起相反的作用。我们将探讨PP 1 β在突触传递中的结构-功能关系和可塑性，重点是PP 1 β C-末端，其中存在一种人PP 1 β从头突变。这些研究将提供PP 1亚型的信号传导机制和结构决定因素，调节它们在突触功能上的独特作用。