Deregulation of RNA metabolism has emerged as one of the key events leading to thedegeneration 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 metabolismaccount for the majority of familiar forms of ALS. In particular, the impact of the ALS-linked mutationsof the RBP FUS on many aspects of RNA-related processes has been vastly investigated. FUS plays apivotal role in splicing regulation and its mutations severely alter the exon composition of transcriptscoding 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 onnon-canonical splicing events that leads to the formation of circular RNAs (circRNAs). We observedaltered levels of circRNAs in FUSP525L MNs and a preferential binding of the mutant protein tointrons flanking downregulated circRNAs and containing inverted Alu repeats. For a subset ofcircRNAs, FUSP525L also impacts their nuclear/cytoplasmic partitioning, confirming its involvementin different processes of RNA metabolism. Finally, we assess the potential of cytoplasmic circRNAsto act as miRNA sponges, with possible implications in ALS pathogenesis.

FUS alters circRNA metabolism in human motor neurons carrying the ALS-linked P525L mutation

ALESSIO COLANTONI;
2023-01-01

Abstract

Deregulation of RNA metabolism has emerged as one of the key events leading to thedegeneration 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 metabolismaccount for the majority of familiar forms of ALS. In particular, the impact of the ALS-linked mutationsof the RBP FUS on many aspects of RNA-related processes has been vastly investigated. FUS plays apivotal role in splicing regulation and its mutations severely alter the exon composition of transcriptscoding 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 onnon-canonical splicing events that leads to the formation of circular RNAs (circRNAs). We observedaltered levels of circRNAs in FUSP525L MNs and a preferential binding of the mutant protein tointrons flanking downregulated circRNAs and containing inverted Alu repeats. For a subset ofcircRNAs, FUSP525L also impacts their nuclear/cytoplasmic partitioning, confirming its involvementin different processes of RNA metabolism. Finally, we assess the potential of cytoplasmic circRNAsto act as miRNA sponges, with possible implications in ALS pathogenesis.
2023
FUS
circRNAs
P525L
ALS
back-splicing
motor neurons
ceRNA
Alu
ADAR
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14245/14661
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