3' UTR variants of ALS-linked RNAs modify subcellular and cellular phenotypes

Abstract

While most human genes express mRNA 3untranslated region (3UTR) variants of different lengths, their impact on cell physiology and disease remains largely unknown. Here, we studied 3UTR length heterogeneity in amyotrophic lateral sclerosis (ALS) and determined that three ALS-linked transcripts exhibit lengthening of their 3UTRs in patient samples. We investigated phenotypical effects in a neuronal cell line expressing these 3UTRs and observed that expression of these unique 3UTRs induces morphological changes at different levels. Among the most expressed 3UTRs variants in ALS, NEFH 3UTR-Long induces the formation of nuclear RNA clusters and SOD1 3UTR-Long diminishes filopodia in the plasma membrane. SQSTM1 3UTR-Long did not show major changes in nuclear RNA clusters or filopodia. This is the first report that suggests that 3UTRs may function independent of the coding region and modify the phenotype of a cell, further expanding the impact of alterations in mRNA biogenesis in ALS.