Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Medical Research Building Room 10.138C , 301 University Blvd, Galveston, TX, 77555-1045, USA.
Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
Acta Neuropathol Commun. 2018 Oct 26;6(1):113. doi: 10.1186/s40478-018-0615-0.
Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with structural and functional alterations of brain cells causing progressive deterioration of memory and other cognitive functions. Recent studies demonstrate that several neurodegenerative diseases, including AD exhibit RNA-binding proteins (RBPs) pathologies, including TAR DNA -binding protein (TDP-43), fused in sarcoma (FUS), superoxide dismutase (SOD1) and T-interacting antigen-1 (TIA-1), highlighting the role of RBPs in neurodegeneration. One such group of RBPs, Musashi proteins comprised of MSI1 and MSI2, has been long studied in neurogenesis and cancer biology. Herein, we have investigated the aggregation properties of MSI1 and MSI2 by in vitro assays, their expression and accumulation as well as their possible interactions with other cellular proteins, such as tau in AD pathology. We have performed atomic force microscopy, Western blot, and immunoprecipitation to demonstrate the aggregation properties of recombinant Musashi proteins. Furthermore, we have studied cortical brain sections from AD (N = 4) and age-matched non-demented subjects (N = 4) by Western blot and immunofluorescence microscopy to investigate MSI1 and MSI2 levels and their localization in human brain tissues. Musashi proteins showed in vitro aggregation properties by forming oligomers. We have observed an increase in Musashi proteins levels in AD brain tissues as compared with age-matched non-demented subjects. Moreover, Musashi proteins are observed to form oligomers in the diseased brain tissues. Interestingly, the co-immunofluorescence study has revealed a change in fluorescence pattern of oligomeric Musashi proteins and tau with a high association in the perinuclear area of the cells suggesting changes in function of Musashi proteins. Our data have demonstrated for the first time that MSI1 and MSI2 are present in an oligomeric state in AD brains compared to the age-matched non-demented subjects and that these large assemblies co-localize with tau contributing to the neurodegenerative pathogenesis.
阿尔茨海默病（AD）是最常见的与脑细胞结构和功能改变相关的神经退行性疾病，导致记忆和其他认知功能的进行性恶化。最近的研究表明，几种神经退行性疾病，包括 AD，表现出 RNA 结合蛋白（RBPs）病理学，包括 TAR DNA 结合蛋白（TDP-43）、融合肉瘤（FUS）、超氧化物歧化酶（SOD1）和 T 相互作用抗原-1（TIA-1），突出了 RBPs 在神经退行性变中的作用。RBPs 中有一组称为 Musashi 蛋白，由 MSI1 和 MSI2 组成，长期以来一直被研究用于神经发生和癌症生物学。在此，我们通过体外测定、表达和积累以及与其他细胞蛋白（如 AD 病理学中的 tau）的可能相互作用，研究了 MSI1 和 MSI2 的聚集特性。我们进行了原子力显微镜、Western blot 和免疫沉淀实验来证明重组 Musashi 蛋白的聚集特性。此外，我们通过 Western blot 和免疫荧光显微镜研究了 AD（N=4）和年龄匹配的非痴呆受试者（N=4）的皮质脑切片，以研究 MSI1 和 MSI2 的水平及其在人脑组织中的定位。Musashi 蛋白通过形成寡聚体表现出体外聚集特性。与年龄匹配的非痴呆受试者相比，我们观察到 AD 脑组织中 Musashi 蛋白水平增加。此外，在患病脑组织中观察到 Musashi 蛋白形成寡聚体。有趣的是，共免疫荧光研究显示寡聚 Musashi 蛋白和 tau 的荧光模式发生变化，细胞核周区有很高的关联，表明 Musashi 蛋白功能发生变化。我们的数据首次证明，与年龄匹配的非痴呆受试者相比，MSI1 和 MSI2 存在于 AD 大脑中的寡聚状态，这些大聚集体与 tau 共定位，导致神经退行性发病机制。
Zotero 插件