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.

中文翻译：

---

核输入受体作为 ALS/FTD 病理相变的看门人

肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 是一系列致命的神经退行性疾病，其特征是朊病毒样 RNA 结合蛋白 (RBP) 的细胞质错误定位和异常相变。TAR DNA 结合蛋白 43 (TDP-43)、融合在肉瘤 (FUS) 中的 TAR DNA 结合蛋白 43 (TDP-43) 和其他核 RBP 在 ALS/FTD 退化神经元细胞质中去污剂不溶性聚集物中的共同积累与核孔功能障碍有关，核细胞质运输机制的其他缺陷。最近的进展表明，除了在蛋白质货物核输入中的典型作用之外，核输入受体 (NIR) 还可以预防和逆转 TDP-43、FUS 和相关朊病毒样 RBP 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、驱动核输入以及与 ALS/FTD 相关的伴侣朊病毒样 RBP。我们还讨论了提高 NIR 水平和开发增强 NIR 变体作为 ALS/FTD 和相关神经退行性蛋白质病治疗策略的前景。