Clustering of Tau fibrils impairs the synaptic composition of α3-Na+/K+-ATPase and AMPA receptors
Clustering of Tau fibrils impairs the synaptic composition of α3-Na+/K+-ATPase and AMPA receptors
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DOI：
10.15252/embj.201899871
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发表时间：
2019-02-01
期刊：
影响因子：
11.4
通讯作者：
Melki, Ronald
中科院分区：
文献类型：
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作者：
Shrivastava, Amulya Nidhi;Redeker, Virginie;Melki, Ronald
Tau蛋白组装体具有类似朊病毒的特性：它们从一个神经元传播到另一个神经元，并通过播种内源性Tau蛋白的聚集来扩增。尽管外源Tau蛋白在朊病毒样传播中起关键作用，但其与幼稚神经元质膜的结合尚不清楚。我们报告了纤原性Tau蛋白在质膜上形成团簇。我们发现原纤维与Na+/K+- atp酶（NKA）和AMPA受体相互作用。聚类的结果是突触上α 3-NKA数量的减少和GluA2-AMPA受体数量的增加。此外，纤原Tau破坏了功能性NKA复合物的稳定性。Tau蛋白和α -突触核蛋白聚集体通常在患者大脑中共存。我们现在展示了这些致病聚集体与α -突触核蛋白原纤维之间的串扰证据，这些串扰显著增强了原纤维Tau聚集和突触定位。我们的研究结果表明，原纤维α -突触核蛋白和Tau蛋白相互作用在质膜失衡神经元稳态中起作用。
Tau assemblies have prion-like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion-like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naive neurons is not understood. We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+-ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of alpha 3-NKA and an increase in the amount of GluA2-AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA complexes. Tau and alpha-synuclein aggregates often co-exist in patients' brains. We now show evidences for cross-talk between these pathogenic aggregates with alpha-synuclein fibrils dramatically enhancing fibrillar Tau clustering and synaptic localization. Our results suggest that fibrillar alpha-synuclein and Tau cross-talk at the plasma membrane imbalance neuronal homeostasis.