Chongfan Technology
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19
2024
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08
Wu Haitao of Nantong University and Chu Bo of Shandong University have shown that the development and survival of cerebellar Purkinje cells are regulated by iron death!
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Splicing GTPase elongation factor Tu GTP binding domain 2 (EFTUD2) ismicrocephaly(MFDM) syndrome, including cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency causes these symptoms is unclear.
On August 16, 2024, Nantong University Wu Haitao and Shandong University Chu Bo jointly communicated inNeuron（IF=14.7）Published online entitled"Spliceosomal GTPase Eftud2 deficiency-triggered ferroptosis leads to Purkinje cell degeneration"'s research paper,The study showedDefective spliceosomal GTPase Eftud2 triggers iron death leading to degeneration of Purkinje cells.
Here, researchers demonstrated that in mouse cerebellar Purkinje cells (PCs)Eftud2Specific ablation of MFDM leads to severe iron death, PC degeneration, dyskinesia, and cerebellar atrophy, all of which are phenotypes observed in patients with MFDM. Mechanically, the Eftud2 promotesScd1andGch1Expression, up-regulation of monounsaturated fatty acid phospholipids, enhance antioxidant activity, thereby inhibiting PC iron death.Importantly, the study identified the transcription factor Atf4 as a downstream target, regulated in a p53-independent manner.PCsAnti-iron death drooping effect in c. inhibition of iron death effectively savedEftud2 Cerebellar defects in cKO mice.The study reveals an important role of Eftud2 in maintaining PC survival, suggesting that pharmacological or genetic suppression of iron death may be a promising therapeutic strategy for diseases caused by Eftud2 deficiency.
In the mammalian nervous system, alternative splicing (AS) is essential for regulating fundamental neural processes such as neural tube patterns, synaptogenesis, membrane physiology, and synaptic plasticity. This process is tightly regulated by spliceosomes and RNA-binding proteins (RBPs), which are essential for the correct expression of genes. Spliceosome dysfunction is associated with a variety of neurodevelopmental and degenerative diseases.Remarkably, including ataxin-2 (ATXN2), neuronal Elav-like protein 3 (Elavl3), and RNA-binding motif protein 17 (RBM17).RBPsThe mutation causes rapid degeneration of Purkinje cells (PCs), suggesting that splicing plays a critical role in maintaining PC survival.
An elongation factor Tu GTP-binding domain containing 2 (Eftud2, also knownSnu114) is the core component of the spliceosome U5 snRNPs and the only GTPase required for RNA splicing. InZebrafishIn the model,Eftud2mutation leads to p53-dependent apoptosis of neural progenitor cells, whileEftud2The absence of, especially in neural crest cells, leads to cell death and craniofacial malformations in mice. EFTUD2 was originally identified as a causative gene for human mandibular facial dysplasia with microcephaly (MFDM), a complex syndrome attributable to heterozygous mutations in EFTUD2 that can lead to loss of function (LOF) and cell death of neural progenitor and neural crest cells, which partly explains the phenotype of human MFDM and EFTUD2 mutant patients.These symptoms includecerebellar hypoplasiaSignificant bradykinesia and impaired social skills in some patients. How EFTUD2 deficiency causes these neurological symptoms remains unclear.
Here, the authors establish a PC-specificEftud2Knockout (KO) mouse model to elucidate the cellular and molecular mechanisms by which Eftud2 deficiency causes cerebellar dysfunction. Eftud2 Conditional KO (cKO) mice exhibit severe iron death, PC degeneration, dyskinesia, and cerebellar atrophy, similar to the phenotype of some MFDM patients.Eftud2 addedmonounsaturated fatty acid(MUFA-PLs) the abundance of phospholipids and promotes stearoyl-CoA (CoA) desaturase 1 by the transcription factor activating transcription factor 4(Atf4) (Scd1) and GTP cyclohydrolase 1 (Gch1), thereby strongly inhibiting the iron death of PCs through a p53-independent pathway. Pharmacological or genetic suppression can effectively rescueEftud2 Defective phenotype observed in cKO mice.The results of this study show that,Eftud2Inhibition of iron death maintains PC survival in a p53-independent manner, and inhibition of iron death may be beneficial for the treatment of Eftud2 deficiency-induced MFDM and related diseases.
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