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ScRNA-seq and MAS-seq in Eftud2-deficient Purkinje cells

ABSTRACT: Spliceosomal GTPase EFTUD2 (Elongation factor Tu GTP binding domain containing 2) is a causative gene for mandibulofacial dysostosis with microcephaly (MFDM) in humans, a complex syndrome with multiple neurological symptoms including cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency contributes to these neurological symptoms remains elusive. In this study, 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 are similar to phenotypes observed in MFDM patients. Mechanistically, Eftud2 promotes the expression of Scd1 and Gch1, upregulates monounsaturated fatty acids-phospholipids (MUFA-PLs), and enhances systematic antioxidant activity, thereby suppressing ferroptotic cell death of PCs. Importantly, inhibiting ferroptosis efficiently rescues PC loss and motor deficits in Eftud2 cKO mice. Our data reveals a novel role of Eftud2 in maintaining the survival of PCs, and that inhibiting ferroptosis via pharmacological or genetic means may be a promising therapeutic strategy for EFTUD2 deficiency-induced MFDM and related disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE252271 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:The endoribonuclease, Dicer, is indispensible for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in mammalian central nervous system. While functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here we report the effect of Cre-loxP mediated conditional deletion of Dicer selectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology prior to postnatal week 5. Thereafter mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements and premature death by postnatal week 9-10. Integrated transcription profiling, histological and functional analyses of cerebella showed that deletion of Dicer in cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state prior to the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders. Four replicate experiments using samples derived from biologically independent pairs of control (mGfap-Cre; Dicer +/flox) and Dicer mutant (mGfap-Cre; Dicer flox/flox) littermate mice (postnatal day 30) were performed with a dye-swap experimental design.

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ScRNA-seq and MAS-seq in Eftud2-deficient Purkinje cells

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