Amyotrophic lateral sclerosis type 6 (ALS6) 是Fused in Sarcoma（FUS）基因突变引发的家族性ALS亚型。FUS突变导致全球蛋白质合成减少，但尚未确定驱动这种现象的机制。在这项研究中，我们使用了ALS6患者衍生的诱导多能干细胞（hIPSCs）来研究ALS6 FUSR521H突变对运动神经元（MNs）的翻译机制的影响。我们发现与他人的研究结果相符，FUSR521H MNs的蛋白质合成减少。此外，当受到氧化应激时，FUSR521H MNs对其更敏感，并显示出TGF-β和mTORC基因通路表达减少的现象。最后，我们展示了IFNγ处理能减少受氧化应激的FUSR521H MNs细胞凋亡，并在一定程度上恢复了FUSR521H MNs的翻译速率。总体而言，这些发现表明功能性的IFNγ应答对于FUS介导的蛋白质合成至关重要，可能通过FUS核转位在ALS6中发挥作用。© 2023 The Authors. 由John Wiley & Sons Ltd代表International Society of Neuropathology出版的《Brain Pathology》发表。

Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUSR521H MNs. Furthermore, FUSR521H MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUSR521H MNs exposed to oxidative stress and partially restores the translation rates in FUSR521H MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.