Inclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer’s disease (AD). The spreading of misfolded tau “seeds” along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease. Previous studies have demonstrated that the Mammalian Suppressor of Tauopathy 2 (MSUT2), an RNA binding protein, modulates tau pathogenesis in a transgenic mouse model. In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate that the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the “ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein” (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology.

由微管相关蛋白 tau (tau) 组成的内含物与一组统称为 tau 病的神经退行性疾病有关，其中包括阿尔茨海默病 (AD)。错误折叠的 tau 蛋白“种子”沿着神经元网络的传播被认为在 tau 蛋白病理学的进展中发挥着至关重要的作用。因此，限制 tau 种子的释放或摄取可能会抑制 tau 病理学的传播，并有可能阻止疾病的进展。先前的研究表明，哺乳动物 Tau 蛋白病抑制因子 2 (MSUT2)（一种 RNA 结合蛋白）在转基因小鼠模型中调节 tau 发病机制。在本研究中，我们使用 tau 播种模型研究了 MSUT2 对 tau 发病机制的影响。我们的研究结果表明，MSUT2 的缺失可以减轻神经元培养物和小鼠模型中人 tau 种子诱发的病理。此外，MSUT2 调节许多基因转录本，包括腺苷受体 1 (A1AR)，我们发现 A1AR 的下调或抑制可调节“具有 SH3 结构域、锚蛋白重复序列​​和 PH 结构域 1 蛋白的 ArfGAP”（ASAP1 ），从而影响致病性 tau 种子内化到神经元中，从而减少 tau 病理学。