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