Translation inhibition corrects aberrant localization of mutant alanine-glyoxylate aminotransferase: possible therapeutic approach for hyperoxaluria

Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte
Ruth BelostotskyYaacov Frishberg

Abstract

Primary hyperoxaluria type 1 is a severe kidney stone disease caused by abnormalities of the peroxisomal alanine-glyoxylate aminotransferase (AGT). The most frequent mutation G170R results in aberrant mitochondrial localization of the active enzyme. To evaluate the population of peroxisome-localized AGT, we developed a quantitative Glow-AGT assay based on the self-assembly split-GFP approach and used it to identify drugs that can correct mislocalization of the mutant protein. In line with previous reports, the Glow-AGT assay showed that mitochondrial transport inhibitors DECA and monensin increased peroxisomal localization of the mutant. Here, we demonstrate that prolonged treatment with the translation elongation inhibitor emetine, a medicinal alkaloid used in treatment of amoebiasis, corrected G170R-AGT mislocalization. Furthermore, emetine reduced the augmented oxalate level in culture media of patient-derived hepatocytes bearing the G170R mutation. A distinct translation inhibitor GC7 had a similar effect on the mutant Glow-AGT relocalization indicating that mild translation inhibition is a promising therapeutic approach for primary hyperoxaluria type 1 caused by AGT misfolding/mistargeting. • There is no effective conserva...Continue Reading

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Citations

Nov 21, 2018·Methods and Applications in Fluorescence·Sergiy V Avilov, Nataliia Aleksandrova
Dec 13, 2018·Expert Opinion on Emerging Drugs·Alexander WeigertBernd Hoppe
Jan 31, 2021·Journal of Personalized Medicine·Maria Dolores Moya-GarzonMonica Diaz-Gavilan
Jun 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Rie KamiyamaDaichi Kamiyama
Nov 7, 2020·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Ruth Belostotsky, Yaacov Frishberg

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Methods Mentioned

BETA
transfection
FACS
flow cytometry
confocal microscopy
protein folding

Software Mentioned

FIJI ImageJ
Flowing
FIJI
Excel
SUnSET
ImageJ
Image Quant LAS

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