1. GAPDH binders as potential drugs for the therapy of polyglutamine diseases: Design of a new screening assay.
- Author
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Lazarev, Vladimir F., Benken, Konstantin A., Semenyuk, Pavel I., Sarantseva, Svetlana V., Bolshakova, Olga I., Mikhaylova, Elena R., Muronetz, Vladimir I., Guzhova, Irina V., and Margulis, Boris A.
- Subjects
GLYCERALDEHYDEPHOSPHATE dehydrogenase ,POLYGLUTAMINE ,DRUG design ,DRUG use testing ,HUNTINGTON disease ,CELL-mediated cytotoxicity ,BIOLOGICAL aggregation - Abstract
Proteins with long polyglutamine repeats form a complex with glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which enhances aggregation and cytotoxicity in models of Huntington disease. The aim of this study was to develop a novel assay for the screening of anti-aggregation compounds with a focus on the aggregation-promoting capacity of GAPDH. The assay includes a pure Q58 polyglutamine fragment, GAPDH, and a transglutaminase that links the two proteins. The feasibility of the new assay was verified using two GAPDH binders, hydroxynonenal and −(−)deprenyl, and the benzothiazole derivative PGL-135 which exhibits anti-aggregation effect. All three substances were shown to reduce aggregation and cytotoxicity in the cell and in the fly model of Spinocerebellar ataxia. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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