The study investigates the role of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) dysfunction in neurodegeneration associated with multiple sclerosis (MS). Using RNA sequencing (RNAseq) and UV-crosslinking immunoprecipitation followed by RNA sequencing (CLIPseq), the researchers found that hnRNP A1 dysfunction leads to differential binding and altered splicing of target RNAs involved in neuronal function and RNA homeostasis. In MS brains, they identified over 550 differentially expressed genes, with most being previously shown to bind hnRNP A1. These changes were also observed in experimental autoimmune encephalomyelitis (EAE) mouse models, where CLIPseq revealed altered RNA binding profiles of hnRNP A1. Further experiments in primary embryonic mouse neurons confirmed that dysfunctional hnRNP A1 causes neurite loss and altered splicing. The study highlights that hnRNP A1 dysfunction disrupts RNA metabolism and promotes neurodegeneration in MS through altered neuronal RNA splicing.The study investigates the role of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) dysfunction in neurodegeneration associated with multiple sclerosis (MS). Using RNA sequencing (RNAseq) and UV-crosslinking immunoprecipitation followed by RNA sequencing (CLIPseq), the researchers found that hnRNP A1 dysfunction leads to differential binding and altered splicing of target RNAs involved in neuronal function and RNA homeostasis. In MS brains, they identified over 550 differentially expressed genes, with most being previously shown to bind hnRNP A1. These changes were also observed in experimental autoimmune encephalomyelitis (EAE) mouse models, where CLIPseq revealed altered RNA binding profiles of hnRNP A1. Further experiments in primary embryonic mouse neurons confirmed that dysfunctional hnRNP A1 causes neurite loss and altered splicing. The study highlights that hnRNP A1 dysfunction disrupts RNA metabolism and promotes neurodegeneration in MS through altered neuronal RNA splicing.