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Chondrocytes maintain cartilage integrity through coordinated regulation of extracellular matrix (ECM) synthesis and remodeling. These processes depend on ECM dynamic interactions, mediated by integrin-based focal adhesions and associated cytoskeletal components. While the roles of core adhesion proteins are well described, the involvement of sarcoglycans (SGs) remains unclear in chondrocytes. Drawing parallels from striated muscle, where the SG subcomplex stabilizes the sarcolemma, we hypothesized that SGs similarly integrate into chondrocyte adhesion complexes. This study investigated the SGs (α, β, γ, δ) expression with cytoskeletal and adhesion proteins, including actin and vinculin, in human chondrocytes cultured by immunofluorescence, qPCR, and siRNA-mediated silencing. All four SG isoforms were expressed in the cytoplasmic and membrane domains, with enrichment at focal adhesion sites. Double labeling revealed SG colocalization with F-actin stress fibers and vinculin, indicating integration into the core adhesion complex. Silencing of each SG resulted in disrupted actin stress fibers, diffuse vinculin distribution, reduced focal plaque number, and a change in cell morphology. These findings support the hypothesis that SGs regulate actin cytoskeletal dynamics and focal contact stabilization. Loss of SG function compromises chondrocyte shape and adhesion, highlighting the importance of these glycoproteins also in non-muscle cells. Full article

Sarcoglycanopathies, also known as limb girdle muscular dystrophy 3-6, are rare muscular dystrophies characterized, although heterogeneous, by high disability, with patients often wheelchair-bound by late adolescence and frequently developing respiratory and cardiac problems. These diseases are currently incurable, emphasizing the importance of effective treatment strategies and the necessity of animal models for drug screening and therapeutic verification. Using the CRISPR/Cas9 genome editing technique, we generated and characterized δ-sarcoglycan and β-sarcoglycan knockout zebrafish lines, which presented a progressive disease phenotype that worsened from a mild larval stage to distinct myopathic features in adulthood. By subjecting the knockout larvae to a viscous swimming medium, we were able to anticipate disease onset. The δ-SG knockout line was further exploited to demonstrate that a δ-SG missense mutant is a substrate for endoplasmic reticulum-associated degradation (ERAD), indicating premature degradation due to protein folding defects. In conclusion, our study underscores the utility of zebrafish in modeling sarcoglycanopathies through either gene knockout or future knock-in techniques. These novel zebrafish lines will not only enhance our understanding of the disease’s pathogenic mechanisms, but will also serve as powerful tools for phenotype-based drug screening, ultimately contributing to the development of a cure for sarcoglycanopathies. Full article

Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in retinal degeneration is not known. Herein, we characterized changes in the retina of the Sgcd knocked-out mouse (KO, Sgcd^−/−). At baseline, we analyzed the retina structure of three-month-old wild-type (WT, Sgcd^+/+) and Sgcd^−/− mice by hematoxylin and eosin (H&E) staining, assessed the Sgcd–protein complex (α-, β-, γ-, and ε-sarcoglycan, and sarcospan) by immunofluorescence (IF) and Western blot (WB), and performed electroretinography. Compared to the WT, Sgcd^−/− mice are five times more likely to have retinal ruptures. Additionally, all the retinal layers are significantly thinner, more so in the inner plexiform layer (IPL). In addition, the number of nuclei in the KO versus the WT is ever so slightly increased. WT mice express Sgcd-protein partners in specific retinal layers, and as expected, KO mice have decreased or no protein expression, with a significant increase in the α subunit. At three months of age, there were no significant differences in the scotopic electroretinographic responses, regarding both a- and b-waves. According to our data, Sgcd^−/− has a phenotype that is compatible with retinal degeneration. Full article