Dysferlin-peptides reallocate mutated dysferlin thereby restoring function.
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 pro...
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2012
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oai:doaj.org-article:cb39ce123be842d29078789a4fcd66512021-11-18T08:08:09ZDysferlin-peptides reallocate mutated dysferlin thereby restoring function.1932-620310.1371/journal.pone.0049603https://doaj.org/article/cb39ce123be842d29078789a4fcd66512012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23185377/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Mutations 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.Verena SchoewelAndreas MargSeverine KunzTim OverkampRomy Siegert CarrazedoUte ZachariasPeter T DanielSimone SpulerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e49603 (2012) |
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DOAJ |
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Medicine R Science Q |
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Medicine R Science Q Verena Schoewel Andreas Marg Severine Kunz Tim Overkamp Romy Siegert Carrazedo Ute Zacharias Peter T Daniel Simone Spuler Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. |
| description |
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. |
| format |
article |
| author |
Verena Schoewel Andreas Marg Severine Kunz Tim Overkamp Romy Siegert Carrazedo Ute Zacharias Peter T Daniel Simone Spuler |
| author_facet |
Verena Schoewel Andreas Marg Severine Kunz Tim Overkamp Romy Siegert Carrazedo Ute Zacharias Peter T Daniel Simone Spuler |
| author_sort |
Verena Schoewel |
| title |
Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. |
| title_short |
Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. |
| title_full |
Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. |
| title_fullStr |
Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. |
| title_full_unstemmed |
Dysferlin-peptides reallocate mutated dysferlin thereby restoring function. |
| title_sort |
dysferlin-peptides reallocate mutated dysferlin thereby restoring function. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/cb39ce123be842d29078789a4fcd6651 |
| work_keys_str_mv |
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