Inhibition of Ubiquitin Proteasome System Rescues the Defective Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1) Protein Causing Chianina Cattle Pseudomyotonia

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  • Elisa Bianchini, From the Departments of Biomedical Sciences and., Italy
  • Stefania Testoni, the Departments of Animal Medicine Production and Health and., Italy
  • Arcangelo Gentile, the Department of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, Italy., Italy
  • Tito Calì, Biology, University of Padova, 35131 Padova, Italy., Italy
  • Denis Ottolini, Biology, University of Padova, 35131 Padova, Italy., Italy
  • Antonello Villa, the Consorzio M.I.A., University of Milano Bicocca, 20900 Monza, Italy., Italy
  • Marisa Brini, Biology, University of Padova, 35131 Padova, Italy., Italy
  • Romeo Betto, the Neuroscience Institute, Consiglio Nazionale delle Ricerche Padova, 35131 Padova, Italy, and., Italy
  • Francesco Mascarello, Comparative Biomedicine and Food Science, University of Padova,35020 Legnaro (Padova), Italy., Italy
  • Dorianna Sandonà, From the Departments of Biomedical Sciences and dorianna.sandona@unipd.it., Italy
  • Roberta Sacchetto, Comparative Biomedicine and Food Science, University of Padova,35020 Legnaro (Padova), Italy, roberta.sacchetto@unipd.it., Italy
  • Poul Nissen

A missense mutation in ATP2A1 gene, encoding sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) protein, causes Chianina cattle congenital pseudomyotonia, an exercise-induced impairment of muscle relaxation. Skeletal muscles of affected cattle are characterized by a selective reduction of SERCA1 in sarcoplasmic reticulum membranes. In this study, we provide evidence that the ubiquitin proteasome system is involved in the reduced density of mutated SERCA1. The treatment with MG132, an inhibitor of ubiquitin proteasome system, rescues the expression level and membrane localization of the SERCA1 mutant in a heterologous cellular model. Cells co-transfected with the Ca(2+)-sensitive probe aequorin show that the rescued SERCA1 mutant exhibits the same ability of wild type to maintain Ca(2+) homeostasis within cells. These data have been confirmed by those obtained ex vivo on adult skeletal muscle fibers from a biopsy from a pseudomyotonia-affected subject. Our data show that the mutation generates a protein most likely corrupted in proper folding but not in catalytic activity. Rescue of mutated SERCA1 to sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca(2+) concentration and prevent the appearance of pathological signs of cattle pseudomyotonia.

Original languageEnglish
JournalJournal of Biological Chemistry
Volume289
Issue48
Pages (from-to)33073-33082
Number of pages10
ISSN0021-9258
DOIs
Publication statusPublished - 28 Nov 2014

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