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Dysferlin-peptides reallocate mutated dysferlin thereby restoring function

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Item Type:Article
Title:Dysferlin-peptides reallocate mutated dysferlin thereby restoring function
Creators Name:Schoewel, V. and Marg, A. and Kunz, S. and Overkamp, T. and Siegert Carrazedo, R. and Zacharias, U. and Daniel, P.T. and Spuler, S.
Abstract:Mutations in the dysferlin gene cause the most frequent adult-onset limb girdle muscular dystrophy, LGMD2B. There is no therapy. Dysferlin is a membrane protein comprised of seven, beta-sheet enriched, C2 domains and is involved in Ca(2+)dependent sarcolemmal repair after minute wounding. On the protein level, point mutations in DYSF lead to misfolding, aggregation within the endoplasmic reticulum, and amyloidogenesis. We aimed to restore functionality by relocating mutant dysferlin. Therefore, we designed short peptides derived from dysferlin itself and labeled them to the cell penetrating peptide TAT. By tracking fluorescently labeled short peptides we show that these dysferlin-peptides localize in the endoplasmic reticulum. There, they are capable of reducing unfolded protein response stress. We demonstrate that the mutant dysferlin regains function in membrane repair in primary human myotubes derived from patients' myoblasts by the laser wounding assay and a novel technique to investigate membrane repair: the interventional atomic force microscopy. Mutant dysferlin abuts to the sarcolemma after peptide treatment. The peptide-mediated approach has not been taken before in the field of muscular dystrophies. Our results could redirect treatment efforts for this condition.
Keywords:Atomic Force Microscopy, Amyloidogenic Proteins, Biopsy, Calcium, Endoplasmic Reticulum, Fluorescent Dyes, Lasers, Membrane Proteins, Missense Mutation, Muscle Proteins, Mutation, Myoblasts, Peptides, Point Mutation, Protein Folding, Tertiary Protein Structure, Unfolded Protein Response, Animals, Mice
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e49603
Date:20 November 2012
Official Publication:https://doi.org/10.1371/journal.pone.0049603
PubMed:View item in PubMed

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