Soliman Ahlam S, Umstead Andrew, Lamp Jared, Vega Irving E
Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States.
Neuroscience Program, Michigan State University, East Lansing, MI, United States.
Front Neurosci. 2024 May 3;18:1373410. doi: 10.3389/fnins.2024.1373410. eCollection 2024.
Tauopathies are characterized by the abnormal buildup of tau protein, with early oligomeric forms associated with neurodegeneration and the later neurofibrillary tangles possibly conferring neuroprotection. The molecular mechanisms governing the formation of these tau species are unclear. Lately, there has been an increased focus on examining the interactions between tau and other proteins, along with their influence on the aggregation of tau. Our previous work revealed EFhd2's association with pathological tau in animal models and tauopathy brains. Herein, we examined the impact of EFhd2 on monomeric and filamentous tau . The results demonstrated that EFhd2 incubation with monomeric full length human tau (hTau40) formed amorphous aggregates, where both EFhd2 and hTau40 colocalized. Moreover, EFhd2 is entangled with arachidonic acid (ARA)-induced filamentous hTau40. Furthermore, EFhd2-induced aggregation with monomeric and filamentous hTau40 is EFhd2 concentration dependent. Using sandwich ELISA assays, we assessed the reactivity of TOC1 and Alz50-two conformation-specific tau antibodies-to EFhd2-hTau40 aggregates (in absence and presence of ARA). No TOC1 signal was detected in EFhd2 aggregates with monomeric hTau40 whereas EFhd2 aggregates with hTau in the presence of ARA showed a higher signal compared to hTau40 filaments. In contrast, EFhd2 aggregates with both monomeric and filamentous hTau40 reduced Alz50 reactivity. Taken together, our results illustrate for the first time that EFhd2, a tau-associated protein, interacts with monomeric and filamentous hTau40 to form large aggregates that are starkly different from tau oligomers and filaments. Given these findings and previous research, we hypothesize that EFhd2 may play a role in the formation of tau aggregates. Nevertheless, further studies are imperative to test this hypothesis.
tau蛋白病的特征是tau蛋白异常积聚，早期寡聚形式与神经退行性变相关，而后期的神经原纤维缠结可能具有神经保护作用。目前尚不清楚这些tau蛋白物种形成的分子机制。最近，人们越来越关注研究tau蛋白与其他蛋白质之间的相互作用，以及它们对tau蛋白聚集的影响。我们之前的研究表明，在动物模型和tau蛋白病大脑中，EFhd2与病理性tau蛋白有关联。在此，我们研究了EFhd2对单体和丝状tau蛋白的影响。结果表明，EFhd2与单体全长人tau蛋白（hTau40）孵育形成无定形聚集体，其中EFhd2和hTau40共定位。此外，EFhd2与花生四烯酸（ARA）诱导的丝状hTau40缠结在一起。此外，EFhd2诱导的与单体和丝状hTau40的聚集呈EFhd2浓度依赖性。我们使用夹心ELISA检测法，评估了TOC1和Alz50（两种构象特异性tau抗体）对EFhd2-hTau40聚集体（有无ARA存在）的反应性。在与单体hTau40形成的EFhd2聚集体中未检测到TOC1信号，而在有ARA存在的情况下与hTau形成的EFhd2聚集体与hTau40细丝相比显示出更高的信号。相比之下，与单体和丝状hTau40形成的EFhd2聚集体降低了Alz50的反应性。综上所述，我们的结果首次表明，一种与tau蛋白相关的蛋白质EFhd2与单体和丝状hTau40相互作用，形成与tau蛋白寡聚体和细丝截然不同的大聚集体。基于这些发现和之前的研究，我们推测EFhd2可能在tau蛋白聚集体的形成中起作用。然而，必须进行进一步的研究来验证这一假设。
