Influence of FTDP-17 mutants on circTau RNAs

Abstract

At least 53 mutations in the microtubule associated protein tau gene (MAPT) have been identified that cause frontotemporal dementia. 47 of these mutations are localized between exons 7 and 13. They could thus affect the formation of circular RNAs (circRNAs) from the MAPT gene that occur through backsplicing from exon 12 to either exon 10 or exon 7. We analyzed representative mutants and found that five FTDP-17 mutations increase the formation of 127 circRNA and three different mutations increase the amount of 1210 circRNA. CircRNAs are translated after undergoing adenosine to inosine RNA editing, catalyzed by ADAR enzymes. We found that the interferon induced ADAR1-p150 isoform has the strongest effect on circTau RNA translation. ADAR1-p150 activity had a stronger effect on circTau RNA expression and strongly decreased 127 circRNA, but unexpectedly increased 1210 circRNA. In both cases, ADAR-activity strongly promoted translation of circTau RNAs. Unexpectedly, we found that the 127 circTau protein interacts with eukaryotic initiation factor 4B (eIF4B), which is reduced by four FTDP-17 mutations located in the second microtubule domain. These are the first studies of the effect of human mutations on circular RNA formation and translation. They show that point mutations influence circRNA expression levels, likely through changes in the secondary pre-mRNA structures. The effect of the mutations is surpassed by editing of the circular RNAs, leading to their translation. Thus, circular RNAs and their editing status should be considered when analyzing FTDP-17 mutations. HighlightsO_LI47/53 known FTDP-17 mutations are located in regions that could influence generation of circular RNAs from the MAPT gene C_LIO_LICircular Tau RNAs are translated after adenosine to inosine RNA editing, most effectively caused by ADAR1-p150 C_LIO_LIFTDP-17 mutations influence both circTau RNA and circTau protein expression levels C_LIO_LICircTau protein expression levels do not correlate with circTau RNA expression levels C_LIO_LICircTau proteins bind to eukaryotic initiation factor 4B, which is antagonized by FTDP-17 mutations in exon 10 C_LI Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/556913v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@94a395org.highwire.dtl.DTLVardef@7fbdc3org.highwire.dtl.DTLVardef@83539eorg.highwire.dtl.DTLVardef@1e6b59e_HPS_FORMAT_FIGEXP M_FIG C_FIG