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Human Molecular Genetics Advance Access published online on November 30, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi432
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 12, 2005
Accepted November 18, 2005

Article

Prevention of oculopharyngeal muscular dystrophy-associated aggregation of nuclear poly(A)-binding protein with a single-domain intracellular antibody

Peter Verheesen 1 *, Anna de Kluijver 2, Silvana van Koningsbruggen 3, Marjolein de Brij 3, Hans J. de Haard 4, Gert-Jan B. van Ommen 3, Silvère M. van der Maarel 3, and C. Theo Verrips 2

1 University of Utrecht, Department of Molecular and Cellular Biology, Padualaan 8, 3584 CH Utrecht, The Netherlands
2 University of Utrecht, Department of Molecular and Cellular Biology, Utrecht, The Netherlands
3 Leiden University Medical Center, Center for Human and Clinical Genetics, Leiden, The Netherlands
4 Ablynx nv, Ghent, Belgium

* To whom correspondence should be addressed.
Peter Verheesen, E-mail: pverheesen{at}hotmail.com


  Abstract

Oculopharyngeal muscular dystrophy (OPMD) belongs to the group of protein aggregation disorders and is caused by extensions of the N-terminal polyalanine stretch of the nuclear poly(A)-binding protein 1 (PABPN1). The presence of PABPN1-containing intranuclear aggregates in skeletal muscle is unique for OPMD and is also observed in transgenic mouse and cell models for OPMD. These models consistently support a direct role for the protein aggregation in OPMD pathogenesis. We have isolated and characterized a diverse panel of single-domain antibody reagents (VHH) recognizing different epitopes in PABPN1. The antibody reagents specifically detect endogenous PABPN1 in cell lysates on Western blot and label PABPN1 in cultured cells and muscle sections. When expressed intracellularly as intrabodies in a cellular model for OPMD, aggregation of PABPN1 was prevented in a dose dependent manner. More importantly yet, these intrabodies could also reduce the presence of already existing aggregates. Given the domain-specificity of VHH-mediated aggregation interference, this approach at least allows the definition of the nucleation-kernel in aggregation-prone proteins, thus facilitating etiological insight in this and other protein aggregation disorders, and ultimately it may well provide useful therapeutic agents.


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