Dendritic spine morphology and the Ubiquitin pathway

树突棘形态和泛素通路

• 批准号: 7201671
• 负责人: Xiaolu Ang Cambronne
• 金额: $ 3.14万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201671
• 关键词: Actins; Acute; Affect; Binding; Biological Assay; Cells; Classification; Complex; Computer software; Cytoskeleton; DNA Sequence Rearrangement; Data; Dendritic Spines; Disease; Dominant-Negative Mutation; Down Syndrome; Down-Regulation; Epilepsy; Excitatory Synapse; F-Actin; F-Box Proteins; Fragile X Syndrome; Head; Hippocampus (Brain); Image; In Vitro; Individual; Investigation; Ligase; Mediating; Molecular; Morphology; N-Methyl-D-Aspartate Receptors; Neurons; Numbers; Pathway interactions; Phosphorylation; Picrotoxin; Proteasome Inhibitor; Protein Overexpression; Protein-Serine-Threonine Kinases; RNA Interference; Reaction; Recruitment Activity; Regulation; Role; SKP Cullin F-Box Protein Ligases; Signal Transduction; Specificity; Structure; Synapses; Synaptic plasticity; TP53 gene; Ubiquitin; Ubiquitination; Vertebral column; base; density; genetic regulatory protein; human PLK1 protein; in vivo; knock-down; nervous system disorder; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; postsynaptic; presynaptic density protein 95; reconstitution; research study; serum-inducible kinase; size; two-photon; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Dendritic spines in excitatory synapses can undergo dynamic actin-based morphological changes associated with synaptic plasticity. Recent examination into the molecular basis of this plasticity uncovered a role for SPAR, a RapGAP that targets to the PSD of dendritic spines. In turn, SPAR stability is regulated by serine/threonine kinase SNK. SNK phosphorylates SPAR, which promotes SPAR degradation through a proteasomal pathway. Nevertheless, the identity of the E3 Ub-ligases that target SPAR and how they are regulated is still unknown. Our investigation into the E3 Ub-ligases that target SPAR to regulate synaptic plasticity includes the following three major efforts: Aim 1 investigates roles for SCF Ub-ligases in SPAR degradation and the activation signals they recognize in the substrate; Aim 2 details a comprehensive approach to identify all E3 Ub-ligases that target SPAR; and Aim 3 examines how depletion of identified candidate E3 Ub-ligases affects dendritic spine morphology in primary hippocampal neurons. In addition to providing concrete evidence for the involvement of the Ub-pathway in the regulation of dendritic spine morphology, identification of the E3 Ub-ligases that mediate SPAR degradation is intrinsic to understanding the mechanism that may underlie a number of disorders associated with abnormal spine morphology and density, including general mental retardation, fragile-X syndrome, Down's syndrome, and epilepsy.

描述（由申请人提供）：兴奋性突触中的树突棘可以经历与突触可塑性相关的基于肌动蛋白的动态形态学变化。最近对这种可塑性的分子基础的研究揭示了SPAR的作用，SPAR是一种靶向树突棘PSD的RapGAP。反过来，SPAR稳定性由丝氨酸/苏氨酸激酶SNK调节。SNK磷酸化SPAR，其通过蛋白酶体途径促进SPAR降解。然而，靶向SPAR的E3 Ub连接酶的身份以及它们如何被调节仍然是未知的。我们对靶向SPAR调节突触可塑性的E3 Ub连接酶的研究主要包括以下三个方面：目的1研究SCF Ub连接酶在SPAR降解中的作用及其在底物中识别的激活信号;目的2详细描述了一种全面的方法来鉴定所有靶向SPAR的E3 Ub连接酶;目的3研究鉴定的候选E3 Ub连接酶的耗尽如何影响原代海马神经元中的树突棘形态。除了提供具体的证据表明，参与调节树突棘形态的Ub-通路，鉴定E3 Ub-连接酶介导的SPAR降解是内在的理解机制，可能是一些疾病的基础异常棘形态和密度，包括一般精神发育迟滞，脆性X综合征，唐氏综合征和癫痫。