Universität zu Köln

Belostotsky, Ruth, Lyakhovetsky, Roman, Sherman, Michael Y., Shkedy, Fanny, Tzvi-Behr, Shimrit, Bar, Roi, Hoppe, Bernd, Reusch, Bjoern, Beck, Bodo B. and Frishberg, Yaacov (2018). Translation inhibition corrects aberrant localization of mutant alanine-glyoxylate aminotransferase: possible therapeutic approach for hyperoxaluria. J. Mol. Med., 96 (7). S. 621 - 631. NEW YORK: SPRINGER. ISSN 1432-1440

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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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Belostotsky, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED Lyakhovetsky, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Sherman, Michael Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shkedy, Fanny UNSPECIFIED UNSPECIFIED UNSPECIFIED Tzvi-Behr, Shimrit UNSPECIFIED UNSPECIFIED UNSPECIFIED Bar, Roi UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Reusch, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frishberg, Yaacov UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-182147
DOI:	10.1007/s00109-018-1651-8
Journal or Publication Title:	J. Mol. Med.
Volume:	96
Number:	7
Page Range:	S. 621 - 631
Date:	2018
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1440
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FOLDING-DEFECTIVE VARIANTS; PROTEIN-SYNTHESIS; PYRIDOXINE; MUTATIONS; EMETINE Multiple languages Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18214