Proteostasis in Neurodegenerative Disease (B180), Schaller Research Group at the University of Heidelberg and DKFZ, Heidelberg, Germany.
German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Center for Molecular Biology of Heidelberg University (ZMBH), Heidelberg, Germany.
EMBO Rep. 2017 Nov;18(11):2051-2066. doi: 10.15252/embr.201744137. Epub 2017 Sep 11.
Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect , where we observed that downregulation of Bin1 in a model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton.
内吞作用是由产生曲率的 BAR 结构域蛋白和肌动蛋白丝的协调聚合来促进的。在生理条件下，已证明 N-BAR 蛋白 Bin1 能够在多种细胞过程中感知和弯曲膜。最近的研究将 Bin1 确定为阿尔茨海默病的风险因素，尽管其在神经退行性变中的可能病理功能目前尚不清楚。在这里，我们报告说 Bin1 不仅塑造了膜，而且还通过其 BAR 结构域直接参与肌动蛋白结合。我们观察到人类 Bin1 具有适度的肌动蛋白成束活性，并描述了其稳定肌动蛋白丝抵抗解聚的能力。此外，Bin1 还参与稳定 tau 诱导的肌动蛋白束，这是阿尔茨海默病的神经病理学特征。我们还提供了这种效应的证据，我们观察到在 tau 病模型中下调 Bin1 会显著减少 tau 诱导的肌动蛋白包含物的出现。总之，这些发现揭示了 Bin1 修饰肌动蛋白动力学的能力，并为 Bin1 和 tau 诱导的肌动蛋白细胞骨架的病理生物学变化之间提供了可能的机制联系。
