Molecular mechanisms of synapse lose by polo kinases

神经元连接的正常发育依赖于精确控制 突触的形成和消除。这些相反的过程也在突触中发挥重要作用。 可塑性，学习和记忆。然而，与目前关于突触发生的大量数据相比， 相对而言，我们对中枢突触丧失的分子机制知之甚少。我们有 最近发现了一种以血清诱导激酶（SNK）为中心的突触丢失的新机制， 波罗家族的丝氨酸-苏氨酸蛋白激酶。在皮层和海马， 通过突触活动，并随后促进兴奋性突触和树突棘（主要 CMS中兴奋性突触的位点）。SNK通过磷酸化作用对突触发挥作用， 特异性突触后底物如SPAR（一种重要的形态原）的泛素依赖性降解 树突棘由于SNK调节突触和棘的数量、结构和组成， 这种激酶对于形成神经元的长期功能特性可能是重要的。我们有 确定了SNK的另一个潜在底物，丰富的突触后Ras调节剂SynGAP。Ras 信号传导对于包括突触可塑性在内的多种神经生物学过程是至关重要的， 发育和保护免受兴奋性毒性损伤。生物化学和分子方法将是 在目标1中使用，以确定SynGAP和SNK是否在物理上相互作用，以及SynGAP是否是 SNK的直接磷酸化底物。在目标2中，我们将分析SNK之间的函数关系 和SynGAP，并确定SNK是否调节神经元中的SynGAP和Ras。最后， 一个假定的SNK/SynGAP/Ras调控网络在调节树突棘形态将被解决 目标3。本提案中描述的实验对于理解 SNK的作用，并可能在突触可塑性，突触发育， 病理性突触缺失阐明这些途径可能具有临床意义， 鉴于新皮层突触丧失是人类神经系统疾病的标志， 神经退行性变，并且是许多形式的痴呆中认知下降的主要相关因素。

The proper development of neuronal connections depends on precisely controlling the balance between formation and elimination of synapses. These opposing processes also play important roles in synaptic plasticity, learning and memory. Compared to the current wealth of data regarding synaptogenesis, however, relatively little is known about the molecular events underlying the loss of central synapses. We have recently identified a novel mechanism of synapse loss centered on the serum-inducible kinase (SNK), a serine-threonine protein kinase of the polo family. In cortex and hippocampus, the short-lived SNK is induced by synaptic activity and subsequently promotes loss of excitatory synapses and dendritic spines (the primary loci of excitatory synapses in the CMS). SNK exerts its effect on synapses via the phosphorylation- and ubiquitin-dependent degradation of specific postsynaptic substrates such as SPAR, an important morphogen for dendritic spines. Because SNK regulates the number, structure and composition of synapses and spines, this kinase is likely to be important for shaping the long-term functional properties of neurons. We have identified an additional potential substrate of SNK, the abundant postsynaptic Ras regulator SynGAP. Ras signaling is of critical importance for a wide variety of neurobiological processes including synaptic plasticity, development, and protection from excitotoxic insults. Biochemical and molecular approaches will be employed in Aim 1 to determine whether SynGAP and SNK physically interact and whether SynGAP is a direct phosphorylation substrate of SNK. In Aim 2 we will analyze the functional relationship between SNK and SynGAP in vitro and determine whether SNK regulates SynGAP and Ras in neurons. Finally, the role of a putative SNK/SynGAP/Ras regulatory network in regulating dendritic spine morphology will be addressed in Aim 3. The experiments described in this proposal are essential for understanding the mechanisms of SNK action and may have broad impact in the fields of synaptic plasticity, synapse development, and pathological synapse loss. Elucidating these pathways is likely to be of clinical significance and highly relevant to public health in view of the fact that neocortical synapse loss is a hallmark of human neurodegeneration and is the major correlate of cognitive decline in many forms of dementia.