title: Soluble expanded PABPN1 promotes cell death in oculopharyngeal muscular dystrophy.
abstract: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease caused by the expansion of a polyalanine repeat (GCG)(8-13) in exon 1 of the PABPN1 gene. Skeletal muscle fibers nuclei from OPMD patients contain insoluble polyalanine expanded PABPN1 (expPABPN1) nuclear aggregates that sequester different cellular components. Whether these aggregates are pathogenic, or the consequence of a molecular defense mechanism, remains controversial in the field of neurodegenerative disorders and OPMD. Our cellular model shows that interfering with the formation of expPABPN1-induced large nuclear aggregates increases the availability of nuclear expPABPN1 and significantly exacerbates cell death. Live microscopy reveals that cells harboring an increased amount of the soluble forms of expPABPN1 are significantly more prone to toxicity than those with nuclear aggregates. This is the first report directly indicating that nuclear aggregation in OPMD may reflect an active process by which cells sequester and inactivate the soluble toxic form of expPABPN1.
authors.affiliation: Center for Study of Brain Disease, CHUM Research Center, Notre-Dame Hospital, J.A. De-Sève Pavilion Y-3633, 1560 Sherbrooke East, Montreal (Québec), Canada H2L 4M1.
authors.forename: Christiane
authors.initials: C
authors.lastname: Messaed
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Aida
authors.initials: A
authors.lastname: Abu-Baker
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Janet
authors.initials: J
authors.lastname: Laganiere
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042622:DNA Repeat Expansion / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D039103:Poly(A)-Binding Protein II / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity*; D011189:Potassium Chloride / Q000494:pharmacology; D011993:Recombinant Fusion Proteins; D012995:Solubility; D014162:Transfection / Q000379:methods
chemical_list: D039103:Poly(A)-Binding Protein II; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D011189:Potassium Chloride