Dendritic spine morphology and the Ubiquitin pathway

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动态肌动蛋白形态学变化。最近对这种可塑性的分子基础的研究发现了SPAR的作用，SPAR是一种靶向树突棘PSD的RapGAP。反过来，SPAR的稳定性由丝氨酸/苏氨酸激酶SNK调节。SNK磷酸化SPAR，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 -连接酶的研究包括以下三个主要方面：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；目标2详细介绍了识别所有针对SPAR的E3 ub连接酶的综合方法；Aim 3研究了确定的候选E3 ub连接酶的耗尽如何影响初级海马神经元的树突棘形态。除了为ub通路参与树突棘形态的调控提供具体证据外，鉴定介导SPAR降解的E3 ub连接酶对于理解与脊柱形态和密度异常相关的许多疾病（包括一般智力低下、脆性x综合征、唐氏综合征和癫痫）的机制至关重要。

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.