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FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation

Deregulation of RNA metabolism has emerged as one of the key events leading to the degeneration of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) disease. Indeed, mutations on RNA-binding proteins (RBPs) or on proteins involved in aspects of RNA metabolism account for the majority of fam...

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Autores principales: Colantoni, Alessio, Capauto, Davide, Alfano, Vincenzo, D’Ambra, Eleonora, D’Uva, Sara, Tartaglia, Gian Gaetano, Morlando, Mariangela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968238/
https://www.ncbi.nlm.nih.gov/pubmed/36834591
http://dx.doi.org/10.3390/ijms24043181
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author Colantoni, Alessio
Capauto, Davide
Alfano, Vincenzo
D’Ambra, Eleonora
D’Uva, Sara
Tartaglia, Gian Gaetano
Morlando, Mariangela
author_facet Colantoni, Alessio
Capauto, Davide
Alfano, Vincenzo
D’Ambra, Eleonora
D’Uva, Sara
Tartaglia, Gian Gaetano
Morlando, Mariangela
author_sort Colantoni, Alessio
collection PubMed
description Deregulation of RNA metabolism has emerged as one of the key events leading to the degeneration of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) disease. Indeed, mutations on RNA-binding proteins (RBPs) or on proteins involved in aspects of RNA metabolism account for the majority of familiar forms of ALS. In particular, the impact of the ALS-linked mutations of the RBP FUS on many aspects of RNA-related processes has been vastly investigated. FUS plays a pivotal role in splicing regulation and its mutations severely alter the exon composition of transcripts coding for proteins involved in neurogenesis, axon guidance, and synaptic activity. In this study, by using in vitro-derived human MNs, we investigate the effect of the P525L FUS mutation on non-canonical splicing events that leads to the formation of circular RNAs (circRNAs). We observed altered levels of circRNAs in FUS(P525L) MNs and a preferential binding of the mutant protein to introns flanking downregulated circRNAs and containing inverted Alu repeats. For a subset of circRNAs, FUS(P525L) also impacts their nuclear/cytoplasmic partitioning, confirming its involvement in different processes of RNA metabolism. Finally, we assess the potential of cytoplasmic circRNAs to act as miRNA sponges, with possible implications in ALS pathogenesis.
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spelling pubmed-99682382023-02-27 FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation Colantoni, Alessio Capauto, Davide Alfano, Vincenzo D’Ambra, Eleonora D’Uva, Sara Tartaglia, Gian Gaetano Morlando, Mariangela Int J Mol Sci Article Deregulation of RNA metabolism has emerged as one of the key events leading to the degeneration of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) disease. Indeed, mutations on RNA-binding proteins (RBPs) or on proteins involved in aspects of RNA metabolism account for the majority of familiar forms of ALS. In particular, the impact of the ALS-linked mutations of the RBP FUS on many aspects of RNA-related processes has been vastly investigated. FUS plays a pivotal role in splicing regulation and its mutations severely alter the exon composition of transcripts coding for proteins involved in neurogenesis, axon guidance, and synaptic activity. In this study, by using in vitro-derived human MNs, we investigate the effect of the P525L FUS mutation on non-canonical splicing events that leads to the formation of circular RNAs (circRNAs). We observed altered levels of circRNAs in FUS(P525L) MNs and a preferential binding of the mutant protein to introns flanking downregulated circRNAs and containing inverted Alu repeats. For a subset of circRNAs, FUS(P525L) also impacts their nuclear/cytoplasmic partitioning, confirming its involvement in different processes of RNA metabolism. Finally, we assess the potential of cytoplasmic circRNAs to act as miRNA sponges, with possible implications in ALS pathogenesis. MDPI 2023-02-06 /pmc/articles/PMC9968238/ /pubmed/36834591 http://dx.doi.org/10.3390/ijms24043181 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Colantoni, Alessio
Capauto, Davide
Alfano, Vincenzo
D’Ambra, Eleonora
D’Uva, Sara
Tartaglia, Gian Gaetano
Morlando, Mariangela
FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation
title FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation
title_full FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation
title_fullStr FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation
title_full_unstemmed FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation
title_short FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation
title_sort fus alters circrna metabolism in human motor neurons carrying the als-linked p525l mutation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968238/
https://www.ncbi.nlm.nih.gov/pubmed/36834591
http://dx.doi.org/10.3390/ijms24043181
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