Nuclear-import receptors (NIRs) engage nuclear-localization signals (NLSs) of polypeptides in the cytoplasm and transport these cargo across the size-selective barrier of the nuclear-pore complex into the nucleoplasm. Beyond this canonical role in nuclear transport, NIRs operate in the cytoplasm to chaperone and disaggregate NLS-bearing clients. Indeed, NIRs can inhibit and reverse functional and deleterious phase transitions of their cargo, including several prominent neurodegenerative disease-linked RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as TDP-43, FUS, EWSR1, TAF15, hnRNPA1, and hnRNPA2. Importantly, elevated NIR expression can mitigate degenerative phenotypes connected to aberrant cytoplasmic aggregation of RBPs with PrLDs. Here, we review recent discoveries that NIRs can also antagonize aberrant interactions and toxicity of arginine-rich, dipeptide-repeat proteins that are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by G₄C₂ hexanucleotide repeat expansions in the first intron of C9ORF72. We also highlight recent findings that multiple NIR family members can prevent and reverse liquid-liquid phase separation of specific clients bearing RGG motifs in an NLS-independent manner. Finally, we discuss strategies to enhance NIR activity or expression, which could have therapeutic utility for several neurodegenerative disorders, including ALS, FTD, multisystem proteinopathy, limbic-predominant age-related TDP-43 encephalopathy, tauopathies, and related diseases.

核输入受体 (NIR) 参与细胞质中多肽的核定位信号 (NLS)，并将这些货物穿过核孔复合物的大小选择性屏障转运到核质中。除了在核运输中的这一典型作用之外，NIR 还在细胞质中发挥作用，以陪伴和分解带有 NLS 的客户。事实上，NIR 可以抑制和逆转其货物的功能性和有害相变，包括几种著名的神经退行性疾病相关 RNA 结合蛋白 (RBP) 和朊病毒样结构域 (PrLD)，例如 TDP-43、FUS、EWSR1、TAF15 、hnRNPA1 和 hnRNPA2。重要的是，NIR 表达升高可以减轻与 PrLD 的 RBP 异常细胞质聚集有关的退行性表型。在这里，我们回顾了最近的发现，即 NIR 还可以拮抗富含精氨酸的二肽重复蛋白的异常相互作用和毒性，这些蛋白与 G ₄ C ₂六核苷酸重复扩展引起的肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 相关。 C9ORF72的第一个内含子。我们还强调了最近的发现，即多个 NIR 家族成员可以以独立于 NLS 的方式阻止和逆转带有 RGG 基序的特定客户的液-液相分离。最后，我们讨论了增强 NIR 活性或表达的策略，这可能对多种神经退行性疾病具有治疗作用，包括 ALS、FTD、多系统蛋白病、边缘主导的年龄相关 TDP-43 脑病、tau蛋白病和相关疾病。