Dendritic spine morphology and the Ubiquitin pathway

兴奋性突触中的树突棘可以经历基于肌动蛋白的动态形态变化 具有突触可塑性。最近对这种可塑性的分子基础的研究发现， Spar，一种针对树突棘的PSD的RapGAP。反过来，Spar的稳定性受以下因素的影响 丝氨酸/苏氨酸激酶SNK。SNK使SPAR磷酸化，从而通过一种 蛋白酶体途径。然而，针对SPAR的E3 Ub-连接酶的身份以及它们是如何 监管仍是个未知数。靶向SPAR调节突触的E3Ub连接酶的研究 可塑性包括以下三个主要工作：Aim 1研究干细胞因子Ub连接酶在Spar中的作用 降解和它们在底物中识别的激活信号；Aim 2详细介绍了 识别所有以SPAR为靶标的E3 Ub-连接酶的方法；目标3检查了如何识别 候选E3Ub连接酶影响原代海马神经元中树突棘的形态。除了……之外 为Ub通路参与树突棘的调节提供具体证据 形态、鉴定介导SPAR降解的E3Ub连接酶是理解 可能导致与脊柱形态异常相关的一系列疾病的机制 密度，包括一般精神发育迟滞、脆性X综合征、唐氏综合症和癫痫。

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.