FUS Mutant Human Motoneurons Display Altered Transcriptome and microRNA Pathways with Implications for ALS Pathogenesis

Riccardo De Santis; Laura Santini; Alessio Colantoni; Giovanna Peruzzi; Valeria de Turris; Vincenzo Alfano; Irene Bozzoni; Alessandro Rosa

FUS Mutant Human Motoneurons Display Altered Transcriptome and microRNA Pathways with Implications for ALS Pathogenesis

2017

Summary: The FUS gene has been linked to amyotrophic lateral sclerosis (ALS). FUS is a ubiquitous RNA-binding protein, and the mechanisms leading to selective motoneuron loss downstream of ALS-linked mutations are largely unknown. We report the transcriptome analysis of human purified motoneurons, obtained from FUS wild-type or mutant isogenic induced pluripotent stem cells (iPSCs). Gene ontology analysis of differentially expressed genes identified significant enrichment of pathways previously associated to sporadic ALS and other neurological diseases. Several microRNAs (miRNAs) were also deregulated in FUS mutant motoneurons, including miR-375, involved in motoneuron survival. We report that relevant targets of miR-375, including the neural RNA-binding protein ELAVL4 and apoptotic factors, are aberrantly increased in FUS mutant motoneurons. Characterization of transcriptome changes in the cell type primarily affected by the disease contributes to the definition of the pathogenic mechanisms of FUS-linked ALS. : The FUS gene is associated to ALS. Rosa and colleagues identified alteration in the transcriptome of hiPSC-derived FUS mutant motoneurons. GO analysis pointed to pathways, such as cell adhesion, previously associated to neurodegenerative diseases. miR-375 impairment downstream of FUS mutation alters RNA metabolism and increases pro-apoptotic factors. Characterization of transcriptome changes in motoneurons contributes to the definition of ALS pathogenic mechanisms. Keywords: induced pluripotent stem cells, amyotrophic lateral sclerosis, FUS/TLS, microRNA, miR-375, motoneuron, ELAVL4, p53, ALS, iPSC

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