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Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease that usually manifests itself within the fifth decade. The most prom-inent symptoms are progressive ptosis, dysphagia, and proximal limb mus-cle weakness. The disorder is caused by trinucleotide (GCG) expansions in the N-terminal part of the poly(A)-binding protein 1 (PABPN1) that result in the extension of a 10-alanine segment by up to seven more alanines. | ễFEBS Journal Effect of oculopharyngeal muscular dystrophy-associated extension of seven alanines on the fibrillation properties of the N-terminal domain of PABPN1 Grit Lodderstedt1 Simone Hess2 Gerd Hause3 Till Scheuermann1 Thomas Scheibel2 and Elisabeth Schwarz1 1 Institut fur Biotechnologie Martin-Luther-Universitat Halle-Wittenberg Halle Germany 2 Technische Universitat Munchen Garching Germany 3 Biozentrum der Martin-Luther-Universitat Halle-Wittenberg Halle Germany Keywords AFM alanine expansions amyloid-like kinetics of fibril formation OPMD Correspondence E. Schwartz Institut fur Biotechnologie Martin-Luther-Universitat Halle-Wittenberg Kurt-Mothes-Str. 3 06120 Halle Germany Fax 49 345 55 27 013 Tel. 49 345 55 24 856 E-mail Elisabeth.Schwarz@biochemtech. uni-halle.de Present address Roche Diagnostics GmbH Penzberg Germany Received 12 September 2006 revised 2 November 2006 accepted 8 November 2006 doi 10.1111 j.1742-4658.2006.05595.x Oculopharyngeal muscular dystrophy OPMD is an autosomal dominant disease that usually manifests itself within the fifth decade. The most prominent symptoms are progressive ptosis dysphagia and proximal limb muscle weakness. The disorder is caused by trinucleotide GCG expansions in the N-terminal part of the poly A -binding protein 1 PABPN1 that result in the extension of a 10-alanine segment by up to seven more alanines. In patients biopsy material displays intranuclear inclusions consisting primarily of PABPN1. Poly L-alanine-dependent fibril formation was studied using the recombinant N-terminal domain of PABPN1. In the case of the protein fragment with the expanded poly L-alanine sequence N- 7 Ala fibril formation could be induced by low amounts of fragmented fibrils serving as seeds. Besides homologous seeds seeds derived from fibrils of the wild-type fragment N-WT also accelerated fibril formation of N- 7 Ala in a concentration-dependent manner. Seed-induced fibrillation of N-WT was considerably slower than that of N- 7 .
