Abstract Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). However, the exact pathogenic mechanism of mutant FUS is not completely understood. FUS is an RNA binding protein (RBP) localized predominantly nuclear, but ALS-linked FUS mutations can affect its nuclear localisation signal impairing its import into the nucleus. This mislocalization to the cytoplasm facilitates FUS aggregation in cytoplasmic inclusions. Therapies targeting post translational modifications are rising as new treatments for ALS, and especially acetylation could have a role in the dynamics of RBPs. Research using histone deacetylase (HDAC) inhibitors in FUS-ALS models showed that HDACs can influence cytoplasmic FUS localization. Inhibition of HDACs could promote acetylation of the FUS RNA binding domain (RRM) and altering its RNA interactions resulting in FUS maintenance in the nucleus. In addition, acetylation of FUS RRMs might also favor or disfavor its incorporation in pathological inclusions. In this review, we summarize and discuss the evidence for a potential role of HDACs in the context of FUS-ALS and we propose a new hypothesis based on this overview.

中文翻译：

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HDAC 抑制剂在 FUS-ALS 中的潜在治疗作用

摘要 FUS 基因突变导致肌萎缩侧索硬化 (ALS-FUS)。然而，突变 FUS 的确切致病机制尚不完全清楚。FUS 是一种主要定位于核的 RNA 结合蛋白 (RBP)，但 ALS 相关的 FUS 突变会影响其核定位信号，从而削弱其进入细胞核的能力。这种对细胞质的错误定位促进了 FUS 在细胞质内含物中的聚集。作为 ALS 的新疗法，针对翻译后修饰的疗法正在兴起，尤其是乙酰化可能在 RBP 的动力学中起作用。在 FUS-ALS 模型中使用组蛋白去乙酰化酶 (HDAC) 抑制剂的研究表明，HDAC 可以影响细胞质 FUS 定位。抑制 HDAC 可以促进 FUS RNA 结合域 (RRM) 的乙酰化并改变其 RNA 相互作用，从而导致 FUS 在细胞核中的维持。此外，FUS RRM 的乙酰化也可能有利于或不利于其纳入病理包涵体。在这篇综述中，我们总结并讨论了 HDAC 在 FUS-ALS 背景下的潜在作用的证据，并基于此概述提出了一个新假设。