2. Academic Validation
  3. Spliceosomal GTPase Eftud2 deficiency-triggered ferroptosis leads to Purkinje cell degeneration

Spliceosomal GTPase Eftud2 deficiency-triggered ferroptosis leads to Purkinje cell degeneration

  • Neuron. 2024 Aug 14:S0896-6273(24)00542-7. doi: 10.1016/j.neuron.2024.07.020.
Guochao Yang 1,  Yinghong Yang 2,  Zhihong Song 3,  Liping Chen 3,  Fengjiao Liu 3,  Ying Li 3,  Shaofei Jiang 3,  Saisai Xue 3,  Jie Pei 3,  Yan Wu 3,  Yuanlin He 4,  Bo Chu 5,  Haitao Wu 6
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 250100 Jinan, China.
  • 3 Department of Neurobiology, Beijing Institute of Basic Medical Sciences, 100850 Beijing, China.
  • 4 State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 211166 Nanjing, China.
  • 5 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 250100 Jinan, China. Electronic address: chubo123@sdu.edu.cn.
  • 6 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; Chinese Institute for Brain Research, 102206 Beijing, China. Electronic address: wuht@bmi.ac.cn.
PMID: 39153477 DOI: 10.1016/j.neuron.2024.07.020
Abstract

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.

Keywords

EFTUD2; MFDM; Purkinje cells; alternative splicing; ferroptosis; mandibulofacial dysostosis with microcephaly.

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