Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, U.S.A.
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, U.S.A.
Mol Neurodegener. 2024 Jan 22;19(1):8. doi: 10.1186/s13024-023-00698-1.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是一种疾病谱上的致命神经退行性疾病，其特征是朊病毒样 RNA 结合蛋白（RBPs）的细胞质定位错误和异常相变。在 ALS/FTD 中，变性神经元细胞质中洗涤剂不溶性聚集体中 TAR DNA 结合蛋白-43（TDP-43）、肉瘤融合（FUS）和其他核 RBPs 的共同积累与核孔功能障碍和核质转运机制的其他缺陷有关。最近的进展表明，除了在核输入蛋白货物的经典作用之外，核输入受体（NIRs）还可以预防和逆转 TDP-43、FUS 和相关朊病毒样 RBPs 的异常相变，并恢复其核定位和功能。在这里，我们展示了 NIR 家族以及它们如何识别货物、驱动核输入以及伴侣与 ALS/FTD 相关的朊病毒样 RBPs。我们还讨论了提高 NIR 水平和开发增强型 NIR 变体作为 ALS/FTD 和相关神经退行性蛋白病治疗策略的前景。
