Tau mislocalization in alpha-synuclein-induced synaptic dysfunction

描述（由申请人提供）：帕金森病（PD）患者的痴呆通常与a-突触核蛋白、淀粉样蛋白？（A?）和tau蛋白。在我们新的初步研究中，海马体的CA1和CA3区域极易受到？-突触核蛋白病理以及PD患者大脑中的tau沉积。澄清细胞间的相互作用？-synuclein和tau将有助于更好地了解PD痴呆的发病机制。有趣的是，在我们的初步研究中，pd相关的A53T突变体a-synuclein蛋白的表达驱动tau蛋白进入树突棘，导致AMPA受体在棘中的丢失，导致记忆丧失。找到突触后的联系？我们将验证A53T -synuclein通过导致tau错误定位到树突棘，从而导致钙调神经磷酸酶和GluR1 S845去磷酸化依赖性AMPA受体内化，从而损害突触后结构和/或功能的中心假设。中心假设将通过两个特定目标进行验证：在specific Aim 1中，我们将进行生化，活体成像，免疫细胞化学和电生理实验，以确定tau错误定位和/或tau过度磷酸化在-synuclein引起的突触后功能障碍中的作用。我们将验证a-synuclein通过tau错定位和tau过度磷酸化导致AMPA受体丢失而诱导突触功能障碍的假设。在具体目标2中，我们将使用药理学，分子生物学，遗传学，影像学和电生理学方法来确定钙调磷酸酶和tau蛋白在？-突触核蛋白诱导AMPA受体内化。我们将测试假设？-synuclein通过tau-和钙调磷酸酶依赖的GluR1亚基c端丝氨酸845的去磷酸化诱导AMPA受体内化。该项目的完成将揭示一个新的突触后级联，该级联导致a-synuclein启动后的功能缺陷，这可能发生在突触前或突触后的位置。揭示的信号步骤可能是未来AD和PD治疗策略的目标。

DESCRIPTION (provided by applicant): Dementia in Parkinson's disease (PD) patients is often associated with pathological changes in a-synuclein, Amyloid ? (A?) and tau proteins. In our new preliminary study, the CA1 and CA3 regions of the hippocampus are highly vulnerable to ?-synuclein pathology as well as tau deposits in the brains from PD patients. Clarifying the cellular interaction between ?-synuclein and tau will help better understand the pathogenesis of PD dementia. Interestingly, in our preliminary studies, the expression of PD-related A53T mutant a-synuclein proteins drives tau proteins to dendritic spines, causes loss of AMPA receptors in spines and results in memory loss. To find a postsynaptic link between ?-synuclein and tau, we will test the central hypothesis that A53T a-synuclein impairs post-synaptic structures and/or functions by causing tau mislocalization to dendritic spines, which subsequently leads to calcineurin- and GluR1 S845 dephosphorylation-dependent AMPA receptor internalization. The central hypothesis will be tested by two specific aims: In Specific Aim 1, we will perform biochemical, live imaging, immunocytochemical and electrophysiological experiments to determine the role of tau mislocalization and/or tau hyperphosphorylation in postsynaptic dysfunction caused by ?-synuclein. We will test the hypothesis that a-synuclein induces synaptic dysfunction by causing loss of AMPA receptor through tau mislocalization and tau hyperphosphorylation. In Specific Aim 2, we will use pharmacological, molecular biological, genetic, imaging and electrophysiological approaches to determine the roles of calcineurin and tau in ?-synuclein- induced AMPA receptor internalization. We will test the hypothesis that ?-synuclein induces AMPA receptor internalization via tau- and calcineurin-dependent dephosphorylation of Serine 845 at the C-terminus of GluR1 subunits. The completion of the proposed project will unravel a new final postsynaptic cascade that leads to functional deficits after a-synuclein initiation, which may occur at either a pre- or post-synaptic location. The unraveled signaling steps may be targeted in future AD and PD therapeutic strategies.