Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice.
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.
Dion
Patrick
P
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.
Shanmugam
Vijayalakshmi
V
Gaspar
Claudia
C
Messaed
Christiane
C
Meijer
Inge
I
Toulouse
André
A
Laganiere
Janet
J
Roussel
Julie
J
Rochefort
Daniel
D
Laganiere
Simon
S
Allen
Carol
C
Karpati
George
G
Bouchard
Jean-Pierre
JP
Brais
Bernard
B
Rouleau
Guy A
GA
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*
D010455:Peptides; D039122:Poly(A)-Binding Protein I; C019529:polyalanine