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Effect of oculopharyngeal muscular dystrophy-associated extension of seven alanines on the fibrillation properties of the N-terminal domain of PABPN1

Title data

Lodderstedt, Grit ; Hess, Simone ; Hause, Gerd ; Scheuermann, Till ; Scheibel, Thomas ; Schwarz, Elisabeth:
Effect of oculopharyngeal muscular dystrophy-associated extension of seven alanines on the fibrillation properties of the N-terminal domain of PABPN1.
In: The FEBS Journal. Vol. 274 (2007) Issue 2 . - pp. 346-355.
ISSN 1742-4658
DOI: https://doi.org/10.1111/j.1742-4658.2006.05595.x

Abstract in another language

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)Ala. Using atomic force microscopy, differences in fibril morphologies between N-WT and N-(+7)Ala were detected. Furthermore, fibrils of N-WT showed a lower resistance against solubilization with the chaotropic agent guanidinium thiocyanate than those from N-(+7)Ala. Our data clearly reveal biophysical differences between fibrils of the two variants that are likely caused by divergent fibril structures.

Further data

Item Type: Article in a journal
Refereed: Yes
Keywords: AFM; alanine expansions; amyloid-like; kinetics of fibril formation; OPMD
Institutions of the University: Faculties
Faculties > Faculty of Engineering Science
Faculties > Faculty of Engineering Science > Chair Biomaterials
Faculties > Faculty of Engineering Science > Chair Biomaterials > Chair Biomaterials - Univ.-Prof. Dr. Thomas Scheibel
Profile Fields > Advanced Fields > Advanced Materials
Profile Fields > Advanced Fields > Molecular Biosciences
Profile Fields > Advanced Fields > Polymer and Colloid Science
Profile Fields > Emerging Fields > Food and Health Sciences
Profile Fields
Profile Fields > Advanced Fields
Profile Fields > Emerging Fields
Result of work at the UBT: Yes
DDC Subjects: 600 Technology, medicine, applied sciences
600 Technology, medicine, applied sciences > 620 Engineering
Date Deposited: 25 Sep 2015 05:35
Last Modified: 26 Nov 2015 10:51
URI: https://eref.uni-bayreuth.de/id/eprint/19546