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

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 conservative treatment to decrease oxalate production in ph1 patients. • chemical chaperones rescue mislocalization of mutant agt and reduce oxalate levels. • we have developed an assay for precise monitoring of the peroxisomal agt. • inhibition of translation by emetine reroutes the mutant protein to peroxisome. • mild translation inhibition is a promising cure for conformational disorders.