title: PABPN1 overexpression leads to upregulation of genes encoding nuclear proteins that are sequestered in oculopharyngeal muscular dystrophy nuclear inclusions.
abstract: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease caused by expanded (GCN)12-17 stretches encoding the N-terminal polyalanine domain of the poly(A) binding protein nuclear 1 (PABPN1). OPMD is characterized by intranuclear inclusions (INIs) in skeletal muscle fibers, which contain PABPN1, molecular chaperones, ubiquitin, proteasome subunits, and poly(A)-mRNA. We describe an adenoviral model of PABPN1 expression that produces INIs in most cells. Microarray analysis revealed that PABPN1 overexpression reproducibly changed the expression of 202 genes. Sixty percent of upregulated genes encode nuclear proteins, including many RNA and DNA binding proteins. Immunofluorescence microscopy revealed that all tested nuclear proteins encoded by eight upregulated genes colocalize with PABPN1 within the INIs: CUGBP1, SFRS3, FKBP1A, HMG2, HNRPA1, PRC1, S100P, and HSP70. In addition, CUGBP1, SFRS3, and FKBP1A were also found in OPMD muscle INIs. This study demonstrates that a large number of nuclear proteins are sequestered in OPMD INIs, which may compromise cellular function.
authors.affiliation: Laboratoire de Neurogénétique, Centre de Recherche du CHUM, Université de Montréal, Montréal, Québec, Canada H2L 4M1.
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Corbeil-Girard
authors.forename: Arnaud F
authors.initials: AF
authors.lastname: Klein
authors.forename: A Marie-Josée
authors.initials: AM
authors.lastname: Sasseville
authors.forename: Hugo
authors.initials: H
authors.lastname: Lavoie
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Dicaire
authors.forename: Anik
authors.initials: A
authors.lastname: Saint-Denis
authors.forename: Martin
authors.initials: M
authors.lastname: Pagé
authors.forename: André
authors.initials: A
authors.lastname: Duranceau
authors.forename: François
authors.initials: F
authors.lastname: Codère
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bouchard
authors.forename: George
authors.initials: G
authors.lastname: Karpati
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Bernard
authors.initials: B
authors.lastname: Massie
authors.forename: Yves
authors.initials: Y
authors.lastname: Langelier
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics*; D039122:Poly(A)-Binding Protein I / Q000096:biosynthesis* / Q000235:genetics*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; D039122:Poly(A)-Binding Protein I