Sarcoglycans (SG) are glycosylated proteins (α-, β-, γ- and δ-SG) which form a key structural complex, essential for the membrane integrity of the striated muscle during contraction. Defects in any one of the sarcoglycan coding genes lead to the severe reduction or even the complete loss of the SG-complex and are responsible for a rare genetic disease known as sarcoglycanopathy1. Most of the reported cases are due to missense mutations that originate a full length but folding-defective protein. We proved that the primary event in these cases is the premature degradation of the folding-defective sarcoglycan, followed by the secondary loss of the wild-type partners, operated by the endoplasmic reticulum-associated degradation. We also demonstrated that many missense mutants retain their function because the whole complex can be properly rescued by skipping the degradation of the mutant2. The knowledge of the pathogenic mechanism of sarcoglycanopathy opened new perspectives for the therapy of this neglected disease allowing to design small molecule-based approaches aimed either to inhibit the degradation of sarcoglycan mutants, or to help their folding. By skipping the disposal process, sarcoglycan mutants can assemble into a functional complex that traffics toward the proper site of action. We successfully tested several of such small molecules in cellular models and, notably, in primary myotubes deriving form patients with sarcoglycanopathy3. We are now developing mouse and zebrafish models for the expression of folding-defective sarcoglycans. These novel vertebrate models of sarcoglycanopathy will be of fundamental help to test in vivo efficacy and safety of the proposed therapeutic approaches. Reference: 1. M. Carotti, C. Fecchio and D. Sandona’, Expert Opin in Orphan Drug, 5, 381 (2017) 2. S. Gastaldello, S. D'Angelo, S. Franzoso, M. Fanin, C. Angelini, R. Betto, D. Sandonà Am J Pathol, 173, 170 (2008) 3. E. Bianchini, M. Fanin, K. Mamchaoui, R. Betto, D. Sandonà, Hum Mol Genet, 23, 3746 (2014)

From the molecular mechanism to novel pharmacological approaches, the story of a muscular dystrophy.

Dorianna Sandona’
;
Marcello Carotti
Membro del Collaboration Group
;
Chiara Fecchio
Membro del Collaboration Group
;
Michela Soardi
Membro del Collaboration Group
2017

Abstract

Sarcoglycans (SG) are glycosylated proteins (α-, β-, γ- and δ-SG) which form a key structural complex, essential for the membrane integrity of the striated muscle during contraction. Defects in any one of the sarcoglycan coding genes lead to the severe reduction or even the complete loss of the SG-complex and are responsible for a rare genetic disease known as sarcoglycanopathy1. Most of the reported cases are due to missense mutations that originate a full length but folding-defective protein. We proved that the primary event in these cases is the premature degradation of the folding-defective sarcoglycan, followed by the secondary loss of the wild-type partners, operated by the endoplasmic reticulum-associated degradation. We also demonstrated that many missense mutants retain their function because the whole complex can be properly rescued by skipping the degradation of the mutant2. The knowledge of the pathogenic mechanism of sarcoglycanopathy opened new perspectives for the therapy of this neglected disease allowing to design small molecule-based approaches aimed either to inhibit the degradation of sarcoglycan mutants, or to help their folding. By skipping the disposal process, sarcoglycan mutants can assemble into a functional complex that traffics toward the proper site of action. We successfully tested several of such small molecules in cellular models and, notably, in primary myotubes deriving form patients with sarcoglycanopathy3. We are now developing mouse and zebrafish models for the expression of folding-defective sarcoglycans. These novel vertebrate models of sarcoglycanopathy will be of fundamental help to test in vivo efficacy and safety of the proposed therapeutic approaches. Reference: 1. M. Carotti, C. Fecchio and D. Sandona’, Expert Opin in Orphan Drug, 5, 381 (2017) 2. S. Gastaldello, S. D'Angelo, S. Franzoso, M. Fanin, C. Angelini, R. Betto, D. Sandonà Am J Pathol, 173, 170 (2008) 3. E. Bianchini, M. Fanin, K. Mamchaoui, R. Betto, D. Sandonà, Hum Mol Genet, 23, 3746 (2014)
2017
INTERNATIONAL SYMPOSIUM-CUM-TRAINING COURSE ON MOLECULAR MEDICINE AND DRUG RESEARCH (MMDR-6)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/3315960
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