The key pathogenetic event of an extremely heterogeneous group of genetic diseases, collectively called Unfolded Protein Diseases (UPDs), is the presence of gene mutations that cause either unfolding or misfolding of a coded protein. This usually leads to either toxic gain of function, because of the presence of protein aggregates, or loss of function because of the premature disposal of the mutated, but potentially functional, protein by the cell’s quality control system (QCS). Type 2D Limb Girdle Muscular Dystrophy (LGMD-2D), a severe myopathy due to defect of the SGCA gene, encoding α-sarcoglycan (α-SG), has been recently included in the list of UPDs. α-SG is a type I membrane protein forming a tetrameric complex together with β-, γ- and δ-SG in the sarcolemma of striated muscle. We have demonstrated that, mutated α-SG is intercepted by the ER quality control, retrotranslocated into the cytosol, polyubiquitylated and degraded by the proteasome. Loss of the protein has dramatic consequences also on the other complex subunits, which are rapidly eliminated, although perfectly normal. Two additional UPDs have been considered to affect striated muscles, such as cattle congenital pseudomyotonia (PMT) and recessive Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT). PMT is due to defects in the ATP2A1 gene coding for sarco(endo)plasmic reticulum Ca2+-ATPase isoform 1 (SERCA1). We have recently demonstrated that cattle PMT is the true counterpart of human Brody’s disease. CPVT has been linked to mutations in CASQ2 and TRDN genes, encoding calsequestrin 2 and triadin, respectively. Despite showing largely different clinical phenotypes both share a common feature, i.e., normal levels of the mutated transcripts and almost undetectable levels of the coded products. Our evidence shows that such proteins, being misfolded, are intercepted by the QCS and degraded by the ubiquitin-proteasome system. Relevant for possible therapeutical treatments, we demonstrate that usually protein mutants retain their function. Importantly, we show that some α-SG and SERCA1 mutants can be rescued by manipulating their degradative pathways, thus providing the basis for new potential therapeutical strategies.

ERAD plays a critical role in three severe muscle diseases.

BIANCHINI, ELISA;DOROTEA, TIZIANO;VALLE, GIORGIA;VOLPE, POMPEO;MASCARELLO, FRANCESCO;SACCHETTO, ROBERTA;SANDONA', DORIANNA
2012

Abstract

The key pathogenetic event of an extremely heterogeneous group of genetic diseases, collectively called Unfolded Protein Diseases (UPDs), is the presence of gene mutations that cause either unfolding or misfolding of a coded protein. This usually leads to either toxic gain of function, because of the presence of protein aggregates, or loss of function because of the premature disposal of the mutated, but potentially functional, protein by the cell’s quality control system (QCS). Type 2D Limb Girdle Muscular Dystrophy (LGMD-2D), a severe myopathy due to defect of the SGCA gene, encoding α-sarcoglycan (α-SG), has been recently included in the list of UPDs. α-SG is a type I membrane protein forming a tetrameric complex together with β-, γ- and δ-SG in the sarcolemma of striated muscle. We have demonstrated that, mutated α-SG is intercepted by the ER quality control, retrotranslocated into the cytosol, polyubiquitylated and degraded by the proteasome. Loss of the protein has dramatic consequences also on the other complex subunits, which are rapidly eliminated, although perfectly normal. Two additional UPDs have been considered to affect striated muscles, such as cattle congenital pseudomyotonia (PMT) and recessive Cathecolaminergic Polymorphic Ventricular Tachycardia (CPVT). PMT is due to defects in the ATP2A1 gene coding for sarco(endo)plasmic reticulum Ca2+-ATPase isoform 1 (SERCA1). We have recently demonstrated that cattle PMT is the true counterpart of human Brody’s disease. CPVT has been linked to mutations in CASQ2 and TRDN genes, encoding calsequestrin 2 and triadin, respectively. Despite showing largely different clinical phenotypes both share a common feature, i.e., normal levels of the mutated transcripts and almost undetectable levels of the coded products. Our evidence shows that such proteins, being misfolded, are intercepted by the QCS and degraded by the ubiquitin-proteasome system. Relevant for possible therapeutical treatments, we demonstrate that usually protein mutants retain their function. Importantly, we show that some α-SG and SERCA1 mutants can be rescued by manipulating their degradative pathways, thus providing the basis for new potential therapeutical strategies.
Protein Quality Control and Ubiquitin Systems in Health and Disease
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2578051
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