Tau mislocalization in alpha-synuclein-induced synaptic dysfunction

α-突触核蛋白诱导的突触功能障碍中的 Tau 蛋白错误定位

• 批准号: 8767417
• 负责人: DEZHI LIAO
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767417
• 关键词: AMPA Receptors; Affect; Alzheimer' s Disease; Amyloid; Antibodies; Biochemical; Biological; Brain; Calcineurin; Calcineurin inhibitor; Dementia; Dendritic Spines; Deposition; Dominant-Negative Mutation; Drug Targeting; DsRed; Endocytosis; Event; Exhibits; FK506; Functional disorder; Future; Genetic; Hippocampus (Brain); Image; Knockout Mice; Life; Link; Location; Mediating; Memory Loss; Molecular; Mus; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Patients; Play; Protein Dephosphorylation; Proteins; Role; Serine; Signal Transduction; Site; Structure; Synapses; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Vertebral column; Viral Vector; alpha synuclein; hippocampal pyramidal neuron; inhibitor/antagonist; mutant; novel; postsynaptic; public health relevance; receptor internalization; research study; response; synuclein; tau Proteins; tau-1

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.

描述（由申请人提供）：帕金森病（PD）患者的痴呆通常与α-突触核蛋白、淀粉样蛋白的病理变化有关？ (A?) 和 tau 蛋白。在我们新的初步研究中，海马的 CA1 和 CA3 区域非常容易受到 β-突触核蛋白病理学以及 PD 患者大脑中 tau 沉积物的影响。阐明 β-突触核蛋白和 tau 蛋白之间的细胞相互作用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α-突触核蛋白的表达会驱动tau蛋白到达树突棘，导致树突棘中AMPA受体的丢失并导致记忆丧失。为了找到 α-突触核蛋白和 tau 之间的突触后联系，我们将测试以下中心假设：A53T α-突触核蛋白通过导致 tau 错误定位到树突棘来损害突触后结构和/或功能，从而导致钙调神经磷酸酶和 GluR1 S845 去磷酸化依赖性 AMPA 受体内化。中心假设将通过两个具体目标进行检验：在具体目标 1 中，我们将进行生化、实时成像、免疫细胞化学和电生理学实验，以确定 tau 错误定位和/或 tau 过度磷酸化在 β-突触核蛋白引起的突触后功能障碍中的作用。我们将检验以下假设：α-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，从而诱导突触功能障碍。在具体目标 2 中，我们将使用药理学、分子生物学、遗传学、成像和电生理学方法来确定钙调磷酸酶和 tau 在 β-突触核蛋白诱导的 AMPA 受体内化中的作用。我们将检验以下假设：α-突触核蛋白通过 GluR1 亚基 C 末端丝氨酸 845 的 tau 和钙调神经磷酸酶依赖性去磷酸化诱导 AMPA 受体内化。拟议项目的完成将揭示一个新的最终突触后级联，该级联会导致α-突触核蛋白启动后的功能缺陷，这可能发生在突触前或突触后位置。未解开的信号传导步骤可能是未来 AD 和 PD 治疗策略的目标。