TY - JOUR
T1 - Influence of FTDP-17 mutants on circular tau RNAs
AU - Margvelani, Giorgi
AU - Welden, Justin R.
AU - Maquera, Andrea Arizaca
AU - Van Eyk, Jennifer E.
AU - Murray, Christopher
AU - Miranda Sardon, Sandra C.
AU - Stamm, Stefan
N1 - Publisher Copyright:
© 2024
PY - 2024/4
Y1 - 2024/4
N2 - 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 occurs 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 12➔7 circRNA and three different mutations increase the amount of 12➔10 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 12➔7 circRNA, but unexpectedly increased 12➔10 circRNA. In both cases, ADAR-activity strongly promoted translation of circTau RNAs. Unexpectedly, we found that the 12➔7 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 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.
AB - 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 occurs 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 12➔7 circRNA and three different mutations increase the amount of 12➔10 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 12➔7 circRNA, but unexpectedly increased 12➔10 circRNA. In both cases, ADAR-activity strongly promoted translation of circTau RNAs. Unexpectedly, we found that the 12➔7 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 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.
KW - Circular RNA
KW - FTDP-17
KW - Frontotemporal dementia
KW - Microtubule associated protein tau
KW - RNA editing
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U2 - 10.1016/j.bbadis.2024.167036
DO - 10.1016/j.bbadis.2024.167036
M3 - Article
C2 - 38286213
AN - SCOPUS:85184800734
SN - 0925-4439
VL - 1870
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 4
M1 - 167036
ER -