Molecular mechanisms of synapse lose by polo kinases

神经元连接的正确发展依赖于准确地控制 突触的形成和消除。这些相反的过程在突触中也起着重要的作用 可塑性、学习和记忆。然而，与目前关于突触发生的丰富数据相比， 对于中枢突触丢失背后的分子事件，人们知之甚少。我们有 最近发现了一种以血清诱导蛋白激酶(SNK)为中心的突触丢失的新机制，即 Polo家族的丝氨酸-苏氨酸蛋白激酶。在大脑皮层和海马区，诱发了短暂的SNK 通过突触活动，随后促进兴奋性突触和树突棘(初级 CMS中兴奋性突触的位置)。SNK通过磷酸化在突触上发挥作用-和 依赖泛素的特定突触后底物的降解，如重要的形态原SPAR 树枝状棘突。因为SNK调节突触和棘突的数量、结构和组成， 这种激酶很可能对塑造神经元的长期功能特性很重要。我们有 发现了SNK的另一个潜在底物，丰富的突触后RAS调节因子SynGAP。RAS 信号对包括突触可塑性在内的多种神经生物学过程至关重要， 发展，并保护免受兴奋性毒性侮辱。生化和分子方法将是 在目标1中用于确定SynGAP和SNK是否在物理上交互，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。最后一点是， 一个可能的SNK/SynGAP/RAS调节网络在调节树突棘形态中被提出 本提案中所描述的实验对于理解 SNK的作用，可能在突触可塑性、突触发育和 病理性突触丢失。阐明这些途径可能具有临床意义和高度的 与公共健康有关，因为新皮质突触丢失是人类 神经退行性变，是许多形式的痴呆症认知能力下降的主要原因。

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.