The porphyrin TMPyP4 inhibits elongation during the noncanonical translation of the FTLD/ALS-associated GGGGCC repeat in the C9orf72 gene

Mori, Kohji; Gotoh, Shiho; Yamashita, Tomoko; Uozumi, Ryota; Kawabe, Yuya; Tagami, Shinji; Kamp, Frits; Nuscher, Brigitte; Edbauer, Dieter; Haass, Christian; Nagai, Yoshitaka und Ikeda, Manabu (2021): The porphyrin TMPyP4 inhibits elongation during the noncanonical translation of the FTLD/ALS-associated GGGGCC repeat in the C9orf72 gene. In: Journal of Biological Chemistry, Bd. 297, Nr. 4, 101120

Abstract

GGGGCC (G(4)C(2)) repeat expansion in the C9orf72 gene has been shown to cause frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Dipeptide repeat proteins produced through repeat -associated non-AUG (RAN) translation are recognized as potential drivers for neurodegeneration. Therefore, selective inhibition of RAN translation could be a therapeutic avenue to treat these neurodegenerative diseases. It was previously known that the porphyrin TMPyP4 binds to G(4)C(2) repeat RNA. However, the consequences of this interaction have not been well characterized. Here, we confirmed that TMPyP4 inhibits C9orf72 G(4)C(2) repeat translation in cellular and in in vitro translation systems. An artificial insertion of an AUG codon failed to cancel the translation inhibition, suggesting that TMPyP4 acts downstream of non-AUG translation initiation. Polysome profiling assays also revealed polysome retention on G(4)C(2) repeat RNA, along with inhibition of translation, indicating that elongating ribosomes stall on G(4)C(2) repeat RNA. Urea-resistant interaction between G(4)C(2) repeat RNA and TMPyP4 likely contributes to this ribosome stalling and thus to selective inhibition of RAN translation. Taken together, our data reveal a novel mode of action of TMPyP4 as an inhibitor of G(4)C(2) repeat translation elongation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198