Department of Neurobiology, Beijing Institute of Basic Medical Sciences, 100850 Beijing, China; Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, 226019 Nantong, China.
Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 250100 Jinan, China.
Neuron. 2024 Oct 23;112(20):3452-3469.e9. doi: 10.1016/j.neuron.2024.07.020. Epub 2024 Aug 16.
Spliceosomal GTPase elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a causative gene for mandibulofacial dysostosis with microcephaly (MFDM) syndrome comprising cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency contributes to these symptoms remains elusive. Here, we demonstrate that specific ablation of Eftud2 in cerebellar Purkinje cells (PCs) in mice results in severe ferroptosis, PC degeneration, dyskinesia, and cerebellar atrophy, which recapitulates phenotypes observed in patients with MFDM. Mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity, thereby suppressing PC ferroptosis. Importantly, we identified transcription factor Atf4 as a downstream target to regulate anti-ferroptosis effects in PCs in a p53-independent manner. Inhibiting ferroptosis efficiently rescued cerebellar deficits in Eftud2 cKO mice. Our data reveal an important role of Eftud2 in maintaining PC survival, showing that pharmacologically or genetically inhibiting ferroptosis may be a promising therapeutic strategy for EFTUD2 deficiency-induced disorders.
剪接体 GTP 酶延伸因子 Tu GTP 结合结构域包含蛋白 2（EFTUD2）是一种导致伴有小头颅畸形的下颌面骨发育不全（MFDM）综合征的致病基因，其特征为小脑发育不良和运动功能障碍。EFTUD2 缺乏如何导致这些症状仍不清楚。在这里，我们证明了在小鼠的小脑浦肯野细胞（PC）中特异性敲除 Eftud2 会导致严重的铁死亡、PC 退化、运动障碍和小脑萎缩，这再现了 MFDM 患者观察到的表型。在机制上，Eftud2 促进 Scd1 和 Gch1 的表达，上调单不饱和脂肪酸磷脂，并增强抗氧化活性，从而抑制 PC 的铁死亡。重要的是，我们确定转录因子 Atf4 作为下游靶点，以非依赖 p53 的方式调节 PC 中的抗铁死亡效应。抑制铁死亡能有效挽救 Eftud2 cKO 小鼠的小脑缺陷。我们的数据揭示了 Eftud2 在维持 PC 存活中的重要作用，表明药理学或基因抑制铁死亡可能是治疗 EFTUD2 缺乏引起的疾病的一种有前途的治疗策略。
