Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
Neuron. 2023 Sep 6;111(17):2660-2674.e9. doi: 10.1016/j.neuron.2023.05.033. Epub 2023 Jun 28.
Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple tauopathies, and it is independent of neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we found that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in tauopathies.
许多 RNA 结合蛋白（RBPs），特别是与 RNA 颗粒相关的 RBPs，可促进神经退行性疾病中的病理性蛋白聚集。在这里，我们证明应激颗粒的核心成分 G3BP2 可直接与 Tau 相互作用并抑制 Tau 聚集。在人脑内，多种 Tau 病中 G3BP2 和 Tau 的相互作用显著增加，并且与阿尔茨海默病（AD）中的神经原纤维缠结（NFT）形成无关。令人惊讶的是，在人类神经元和脑类器官中敲低 G3BP2 后 Tau 病理显著升高。此外，我们发现 G3BP2 掩盖了 Tau 的微管结合区（MTBR），从而抑制 Tau 聚集。我们的研究定义了 RBPs 的一个新作用，即作为 Tau 病中 Tau 聚集的防御线。
