Sarcoglycanopathies: Molecular Pathogenesis and Therapeutic Prospects

expert reviews http://www.expertreviews.org/ in molecular medicine Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects Dorianna Sandona` 1 and Romeo Betto2,* Sarcoglycanopathies are a group of autosomal recessive muscle-wasting disorders caused by genetic defects in one of four cell membrane glycoproteins, a-, b-, g-ord-sarcoglycan. These four sarcoglycans form a subcomplex that is closely linked to the major dystrophin-associated protein complex, which is essential for membrane integrity during muscle contraction and provides a scaffold for important signalling molecules. Proper assembly, trafficking and targeting of the sarcoglycan complex is of vital importance, and mutations that severely perturb tetramer formation and localisation result in sarcoglycanopathy. Gene defects in one sarcoglycan cause the absence or reduced concentration of the other subunits. Most genetic defects generate mutated proteins that are degraded through the cell’s quality control system; however, in many cases, conformational modifications do not affect the function of the protein, yet it is recognised as misfolded and prematurely degraded. Recent evidence shows that misfolded sarcoglycans could be rescued to the cell membrane by assisting their maturation along the ER secretory pathway. This review summarises the etiopathogenesis of sarcoglycanopathies and highlights the quality control machinery as a potential pharmacological target for therapy of these genetic disorders. Sarcoglycanopathies are autosomal recessive muscle. The sarcoglycan complex, whose role is muscle-wasting disorders that result only now being revealed, is a component of a from genetic defects of four transmembrane major complex formed by dystrophin at glycoproteins, a-, b-, g- and d-sarcoglycan. costameres in the cell membrane (Refs 1, 2, 3, These four subunits form a distinct complex at 4). Sarcoglycanopathies are included in a large the cell membrane of skeletal and cardiac group of limb-girdle muscular dystrophy 1Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy. 2C.N.R. Institute of Neuroscience, Neuromuscular Biology and Physiopathology, 35121 Padova, Italy. *Corresponding author: Romeo Betto, C.N.R. Institute of Neuroscience, Neuromuscular Biology and Physiopathology, Viale Giuseppe Colombo 3, 35121 Padova, Italy. Tel: +39 049 8276027; Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects Fax: +39 049 8276040; E-mail: [email protected] 1 Accession information: doi:10.1017/S1462399409001203; Vol. 11; e28; September 2009 & Cambridge University Press 2009. Re-use permitted under a Creative Commons Licence–by-nc-sa. expert reviews http://www.expertreviews.org/ in molecular medicine (LGMD) because these progressive muscle maturation process along the ER secretory disorders predominantly affect proximal pathway (Refs 13, 14). The purpose of this muscles around the scapular and the pelvic review is to provide a comprehensive overview girdles. Mutations in individual sarcoglycans of the molecular organisation of the sarcoglycan are responsible for LGMD-2C (g-sarcoglycan), complex and of the pathogenetic events causing LGMD-2D (a-sarcoglycan), LGMD-2E (b- the disease. Novel therapeutic strategies for the sarcoglycan) and LGMD-2F (d-sarcoglycan) treatment of sarcoglycanopathies based on (Refs 5, 6, 7, 8, 9). The clinical phenotype of interference of the ER-processing machinery are sarcoglycanopathies is very heterogeneous, and also evaluated. age of onset, rate of progression and severity can vary between and within affected families The dystrophin–glycoprotein complex (Ref. 10). In general, the disease is characterised The four sarcoglycans form a tetrameric by progressive weakness and degeneration of subcomplex within the multimeric complex skeletal muscle, leading to loss of ambulation, based on dystrophin in the cell membrane of difficulties in breathing and often premature skeletal and cardiac muscle. Dystrophin is a death. The majority of sarcoglycanopathies are large actin-binding cytoskeletal protein that is associated with missense mutations that essential for the organisation of the cell- generate substitution of single residues that membrane-associated dystrophin–glycoprotein could lead to a misfolded protein. Analysis of complex (DGC). The DGC is enriched in muscle samples from patients showed that costameres, which are specialised cytoskeletal these mutations result in either the complete structures connecting the plasma membrane absence or the presence of only trace amounts and Z discs of peripheral myofibrils (Refs 2, 15). of the protein in the cell membrane. Dystrophin is composed of four distinct Sarcoglycans are transmembrane proteins that functional domains: the N-terminal actin- mature in the endoplasmic reticulum (ER) binding domain, a long central domain where nascent proteins reach their native containing 24 spectrin-like repeats, a cysteine- conformation through the activity of an efficient rich domain and the C-terminal domain. The quality control system. Misfolded proteins are protein forms a tight link with the actin identified by the quality control system and cytoskeleton through the N-terminal domain, retrotranslocated to the cytosol for proteasomal an association reinforced by additional binding degradation through the ER-associated protein sites within some spectrin repeats (Ref. 1). At degradation (ERAD) pathway (Refs 11, 12). the distal region of the protein, dystrophin Occasionally, defective proteins may pass forms, via its cysteine-rich domain, a tight the quality control and reach the cell association with the transmembrane protein membrane, where, since they are nonfunctional b-dystroglycan, which in turn is strongly linked and thus unstable, they are dismantled and to the extracellular a-dystroglycan (Fig. 1). The degraded. Defects in each sarcoglycan have two dystroglycans are products of a single gene destabilising consequences on the entire that is post-translationally cleaved into two sarcoglycan complex. Therefore, the subunits (Ref. 17). The highly glycosylated a- pathogenetic mechanisms may comprise: (1) the dystroglycan forms a strong interaction with processing of defective sarcoglycan subunits; (2) laminin a2, a major constituent of muscle fibre the inability to assemble into a complete basement membrane. Thus, the backbone complex; or (3) the targeting of a dysfunctional formed by dystrophin, dystroglycans and sarcoglycan complex to the cell membrane. laminin a2 represents a transmembrane Sequence analysis of sarcoglycans indicated structure directly connecting the actin that although many missense mutations might cytoskeleton to the extracellular matrix. The not have functional consequences, they are localisation of DGC in line with costameres is intercepted by the quality control system, assured by the association of b-dystroglycan which significantly slows their processing and and dystrophin to two ankyrins (B and G), results in the disposal of the mutant protein. which are components of the subsarcolemmal Recent evidence shows that these misfolded cytoskeleton (Ref. 18). The DGC is thus thought Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects ‘functional’ sarcoglycans could be rescued to to provide structural support to the plasma the cell membrane by assisting them in the membrane and to protect it from the 2 Accession information: doi:10.1017/S1462399409001203; Vol. 11; e28; September 2009 & Cambridge University Press 2009. Re-use permitted under a Creative Commons Licence–by-nc-sa. expert reviews http://www.expertreviews.org/ in molecular medicine Laminin α2 α-Dystroglycan Putative partners of DGC Sarcoglycans α O-glycan Extracellular β Biglycan δ γ Perlecan N-glycan Rapsyn β Transmembrane -Dystroglycan Integrins Plasma membrane 16 kDa vH+-ATPase Caveolin Intracellular Sarcospan γ-filamin Syncoilin nNOS Ankyrin Spectrin Dystrophin Syn Plectin Dystrobrevin Syn Actin filament The dystrophin–glycoprotein complex Expert Reviews in Molecular Medicine © Cambridge University Press 2009 Figure 1. The dystrophin–glycoprotein complex. Simplified scheme of dystrophin–glycoprotein complex (DGC) organisation. Dystrophin is localised in the cytoplasmic face of skeletal and cardiac cell membranes. Dystrophin binds actin filaments through two specific binding sites in its C-terminal domain and sites in the spectrin-like-repeat portion. The cysteine-rich domain assures the binding of dystrophin to the transmembrane b-dystroglycan, which in turn associates extracellularly with a-dystroglycan (blue box). a- dystroglycan interacts with laminin a2 and other cell matrix components, completing the backbone of the DGC. The sarcoglycan–sarcospan complex (light blue box), forms a lateral association with dystroglycans. N-glycan and O-glycan indicate, respectively, the N- and O-glycosylation moieties post-translationally added to sarcoglycans and dystroglycans. Additional sarcoglycan partners have been proposed (not all indicated), both intracellularly and extracellularly. Dystrobrevin, syntrophin (Syn) and neuronal nitric oxide synthase (nNOS) are intracellular components of the DGC. Many other proteins have been indicated to interact with DGC, either permanently or dynamically; a few of these are indicated. For a complete list of DGC components the reader should refer Refs 1, 2, 15, 16. mechanical stress of contractile activity by (DMD) and the milder Becker muscular transmitting the lateral tension generated by dystrophy (BMD), whereas defects of laminin muscle

Load more