Tau mislocalization in alpha-synuclein-induced synaptic dysfunction

描述(申请人提供)：帕金森氏病(PD)患者的痴呆症通常与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，海马区的CA1和CA3区非常容易受到？-突触核蛋白病理以及帕金森病患者大脑中tau沉积的影响。阐明β-突触核蛋白和tau之间的细胞相互作用将有助于更好地理解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突变型α-突触核蛋白的表达将tau蛋白驱动到树突棘，导致脊椎中AMPA受体的丧失，并导致记忆丧失。为了找到α-突触核蛋白和tau之间的突触后联系，我们将检验这一中心假设，即A53T a-突触核蛋白通过导致tau错误定位于树突棘而损害突触后结构和/或功能，从而导致钙调神经磷酸酶和GluR1 S845去磷酸化依赖的AMPA受体内化。中心假说将通过两个特定的目标来检验：在特定的目标1，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过度磷酸化在由？-突触核蛋白引起的突触后功能障碍中的作用。我们将验证a-突触核蛋白通过tau错误定位和tau过度磷酸化导致AMPA受体丢失而导致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、成像学和电生理学的方法来确定钙调神经磷酸酶和tau在突触核蛋白诱导的AMPA受体内化中的作用。我们将验证这样的假设，即-突触核蛋白通过依赖tau和钙调神经磷酸酶对GluR1亚基C末端的丝氨酸845去磷酸化来诱导AMPA受体内化。拟议项目的完成将解开一个新的最终突触后级联反应，导致α-突触核蛋白启动后的功能缺陷，可能发生在突触前或突触后位置。这些被解开的信号步骤可能成为未来AD和PD治疗策略的靶点。

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.