title: GAPDH binders as potential drugs for the therapy of polyglutamine diseases: design of a new screening assay.
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.
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg, Russia. Electronic address: vl.lazarev@gmail.com.
authors.forename: Vladimir F
authors.initials: VF
authors.lastname: Lazarev
authors.affiliation: Department of Cytology and Histology, St.-Petersburg State University, St. Petersburg, Russia.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Benken
authors.affiliation: Belozersky Institute of Physico-Chemical Biology of Moscow State University, Moscow, Russia.
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Semenyuk
authors.affiliation: Petersburg Nuclear Physics Institute, National Research Centre "Kurchatov Institute", Gatchina, Russia.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Sarantseva
authors.affiliation: Petersburg Nuclear Physics Institute, National Research Centre "Kurchatov Institute", Gatchina, Russia.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Bolshakova
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Mikhaylova
authors.affiliation: Belozersky Institute of Physico-Chemical Biology of Moscow State University, Moscow, Russia.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Muronetz
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Guzhova
authors.affiliation: Institute of Cytology of Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Boris A
authors.initials: BA
authors.lastname: Margulis
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000379:methods*; D004195:Disease Models, Animal; D004330:Drosophila; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006816:Huntington Disease / Q000175:diagnosis / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*
chemical_list: D010455:Peptides; C097188:polyglutamine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases
keywords: Aggregation assay; Drug; Glyceraldehydes-3-phosphate dehydrogenase; Polyglutamine diseases; Small molecule; Therapeutic target; Transgenic Drosophila; Transglutaminase