Research ArticleMuscular Dystrophy

Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy

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Science Translational Medicine  20 Aug 2014:
Vol. 6, Issue 250, pp. 250ra112
DOI: 10.1126/scitranslmed.3009612

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Proteasome Inhibitors for Patients with Muscular Dystrophy

Many patients affected by muscular dystrophies due to dysferlin deficiency carry pathogenic dysferlin alleles encoding missense mutated proteins, which are degraded by the proteasome. In vitro evidence suggests that such proteins might be functional if salvaged from degradation. Administration of a proteasome inhibitor to three patients harboring a homozygous dysferlin missense mutation led to a marked increase in dysferlin in skeletal muscle and monocytes (Azakir et al.). The salvaged protein became correctly localized to the sarcolemma in muscle biopsies and retained biological activity in patient-derived myoblasts. These results lay the groundwork for long-term studies of proteasomal inhibitors for treating dysferlinopathies and possibly other genetic diseases.


No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell’s quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases.

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