title: Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.
abstract: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6-aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub-effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N-terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti-aggregation molecules.
authors.affiliation: mRNA Regulation and Development, Institut de Génétique Humaine, CNRS UPR 1142, Montpellier Cedex 5, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barbezier
authors.forename: Aymeric
authors.initials: A
authors.lastname: Chartier
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bidet
authors.forename: Anja
authors.initials: A
authors.lastname: Buttstedt
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisset
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.forename: Marc
authors.initials: M
authors.lastname: Blondel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schwarz
authors.forename: Martine
authors.initials: M
authors.lastname: Simonelig
mesh_terms: D000818:Animals; D004330:Drosophila / Q000254:growth & development / Q000378:metabolism; D006143:Guanabenz / Q000627:therapeutic use*; D007814:Larva / Q000378:metabolism; D039141:Muscular Dystrophy, Oculopharyngeal / Q000188:drug therapy / Q000378:metabolism*; D010617:Phenanthridines / Q000627:therapeutic use*; D010641:Phenotype; D039103:Poly(A)-Binding Protein II / Q000378:metabolism*; D017096:Prion Diseases / Q000188:drug therapy; D017510:Protein Folding; D012335:RNA, Ribosomal / Q000378:metabolism
chemical_list: C549408:6-aminophenanthridine; D010617:Phenanthridines; D039103:Poly(A)-Binding Protein II; D012335:RNA, Ribosomal; D006143:Guanabenz