TY - JOUR
T1 - Therapeutic potential of proteasome inhibition in Duchenne and Becker muscular dystrophies
AU - Gazzerro, Elisabetta
AU - Assereto, Stefania
AU - Bonetto, Andrea
AU - Sotgia, Federica
AU - Scarfi, Sonia
AU - Pistorio, Angela
AU - Bonuccelli, Gloria
AU - Cilli, Michele
AU - Bruno, Claudio
AU - Zara, Federico
AU - Lisanti, Michael P.
AU - Minetti, Carlo
PY - 2010/4
Y1 - 2010/4
N2 - Duchenne muscular dystrophy (DMD) and its milder allelic variant, Becker muscular dystrophy (BMD), result from mutations of the dystrophin gene and lead to progressive muscle deterioration. Enhanced activation of proteasomal degradation underlies critical steps in the pathogenesis of the DMD/BMD dystrophic process. Previously, we demonstrated that treatment with the proteasome inhibitor MG-132 rescues the cell membrane localization of dystrophin and the dystrophin glycoprotein complex in mdx mice, a natural genetic mouse model of DMD. The current work aims to thoroughly define the therapeutic potential in dystrophinopathies of Velcade, a drug that selectively blocks the ubiquitin-proteasome pathway. Velcade is particularly intriguing since it has been approved for the treatment of multiple myeloma. Therefore, its side effects in humans have been explored. Velcade effects were analyzed through two independent methodological approaches. First, we administered the drug systemically in mdx mice over a 2-week period. In this system, Velcade restores the membrane expression of dystrophin and dystrophin glycoprotein complex members and improves the dystrophic phenotype. In a second approach, we treated with the compound explants from muscle biopsies of DMD or BMD patients. We show that the inhibition of the proteasome pathway up-regulates dystrophin , α-sarcoglycan , and β-dystroglycan protein levels in explants from BMD patients , whereas it increases the proteins of the dystrophin glycoprotein complex in DMD cases.
AB - Duchenne muscular dystrophy (DMD) and its milder allelic variant, Becker muscular dystrophy (BMD), result from mutations of the dystrophin gene and lead to progressive muscle deterioration. Enhanced activation of proteasomal degradation underlies critical steps in the pathogenesis of the DMD/BMD dystrophic process. Previously, we demonstrated that treatment with the proteasome inhibitor MG-132 rescues the cell membrane localization of dystrophin and the dystrophin glycoprotein complex in mdx mice, a natural genetic mouse model of DMD. The current work aims to thoroughly define the therapeutic potential in dystrophinopathies of Velcade, a drug that selectively blocks the ubiquitin-proteasome pathway. Velcade is particularly intriguing since it has been approved for the treatment of multiple myeloma. Therefore, its side effects in humans have been explored. Velcade effects were analyzed through two independent methodological approaches. First, we administered the drug systemically in mdx mice over a 2-week period. In this system, Velcade restores the membrane expression of dystrophin and dystrophin glycoprotein complex members and improves the dystrophic phenotype. In a second approach, we treated with the compound explants from muscle biopsies of DMD or BMD patients. We show that the inhibition of the proteasome pathway up-regulates dystrophin , α-sarcoglycan , and β-dystroglycan protein levels in explants from BMD patients , whereas it increases the proteins of the dystrophin glycoprotein complex in DMD cases.
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U2 - 10.2353/ajpath.2010.090468
DO - 10.2353/ajpath.2010.090468
M3 - Article
C2 - 20304949
AN - SCOPUS:77950583657
VL - 176
SP - 1863
EP - 1877
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -