title: Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice.
abstract: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder caused by a (GCG)n trinucleotide repeat expansion in the poly(A) binding protein nuclear-1 (PABPN1) gene, which in turn leads to an expanded polyalanine tract in the protein. We generated transgenic mice expressing either the wild type or the expanded form of human PABPN1, and transgenic animals with the expanded form showed clear signs of abnormal limb clasping, muscle weakness, coordination deficits, and peripheral nerves alterations. Analysis of mitotic and postmitotic tissues in those transgenic animals revealed ubiquitinated PABPN1-positive intranuclear inclusions (INIs) in neuronal cells. This latter observation led us to test and confirm the presence of similar INIs in postmortem brain sections from an OPMD patient. Our results indicate that expanded PABPN1, presumably via the toxic effects of its polyalanine tract, can lead to inclusion formation and neurodegeneration in both the mouse and the human.
authors.affiliation: McGill University Health Center Research Institute and the Centre for Research in Neurosciences, McGill University, 1650 Cedar Avenue (L7-224), Montréal, Québec, Canada, H3G 1A4.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dion
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Shanmugam
authors.forename: Claudia
authors.initials: C
authors.lastname: Gaspar
authors.forename: Christiane
authors.initials: C
authors.lastname: Messaed
authors.forename: Inge
authors.initials: I
authors.lastname: Meijer
authors.forename: André
authors.initials: A
authors.lastname: Toulouse
authors.forename: Janet
authors.initials: J
authors.lastname: Laganiere
authors.forename: Julie
authors.initials: J
authors.lastname: Roussel
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.forename: Simon
authors.initials: S
authors.lastname: Laganiere
authors.forename: Carol
authors.initials: C
authors.lastname: Allen
authors.forename: George
authors.initials: G
authors.lastname: Karpati
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bouchard
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018908:Muscle Weakness / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000502:physiology; D039122:Poly(A)-Binding Protein I / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D010455:Peptides; D039122:Poly(A)-Binding Protein I; C019529:polyalanine