Puangmalai Nicha, Aday Abbigael E, Samples Madison, Bhatt Nemil, Cascio Filippa Lo, Marcatti Michela, Park Suhyeorn J, Fung Leiana, Jerez Cynthia, Penalva Luiz O, Zhao Yingxin, Hao Haiping, Lugano Doreen, Kayed Rakez, Montalbano Mauro
Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA; Departments of Neurology, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA.
Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA; Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA.
Prog Neurobiol. 2025 Apr;247:102742. doi: 10.1016/j.pneurobio.2025.102742. Epub 2025 Mar 8.
Alzheimer's disease (AD) is marked by cytoplasmic proteinopathies, primarily involving misfolded Tau protein. Pathogenic Tau species, such as soluble oligomers and fibrils, disrupt RNA metabolism, though the mechanisms are unclear. Recent research indicates that RNA has a crucial role in Tau aggregation. Our study builds on this by noting significant co-deposition of RNA-Binding Proteins (RBPs) with Tau in AD and Frontotemporal dementia (FTLD) brains. Using molecular and cellular techniques, we investigate the interaction between RNA dynamics and Tau aggregation, focusing on the localization and aggregation of Tau and RBPs, particularly Musashi (MSI), within neuronal nuclei. Through cyto-fluorometric, biochemical, and cellular assays, we reveal the importance of Tau/RBP interplay in primary cortical neurons expressing wild-type and mutant Tau. Pathogenic Tau oligomers alter MSI protein localization and function, causing cytoplasmic and nuclear aggregation. Mass spectrometry of the MSI1 nuclear interactome in Tau models shows disrupted RNA metabolism pathways, including ribosomal biogenesis, RNA splicing, and protein folding. Moreover, RNA immunoprecipitation assay revealed a remarkable impact of mutant P301L Tau on MSI1 ability to bind RNA targets. These findings highlight potential targets for early neurodegenerative therapeutic interventions.
阿尔茨海默病（AD）的特征是细胞质蛋白病，主要涉及错误折叠的 Tau 蛋白。致病性 Tau 种类，如可溶性寡聚体和纤维，会破坏 RNA 代谢，但其机制尚不清楚。最近的研究表明，RNA 在 Tau 聚集过程中起着关键作用。我们的研究在此基础上展开，注意到在 AD 和额颞叶痴呆（FTLD）大脑中，RNA 结合蛋白（RBPs）与 Tau 存在显著的共沉积现象。我们运用分子和细胞技术，研究 RNA 动态与 Tau 聚集之间的相互作用，重点关注 Tau 和 RBPs，特别是 Musashi（MSI）在神经元细胞核内的定位和聚集。通过细胞荧光分析、生化分析和细胞实验，我们揭示了 Tau/RBP 相互作用在表达野生型和突变型 Tau 的原代皮质神经元中的重要性。致病性 Tau 寡聚体会改变 MSI 蛋白的定位和功能，导致细胞质和细胞核聚集。Tau 模型中 MSI1 核相互作用组的质谱分析显示，RNA 代谢途径受到破坏，包括核糖体生物合成、RNA 剪接和蛋白质折叠。此外，RNA 免疫沉淀实验表明，突变型 P301L Tau 对 MSI1 结合 RNA 靶点的能力有显著影响。这些发现突出了早期神经退行性治疗干预的潜在靶点。
