Zebrafish lgals3a mutants as models for Arrhythmogenic Cardiomyopathy related phenotypes

Arrhythmogenic cardiomyopathy (AC) is a rare hereditary cardiac disorder characterized by fibro-fatty substitution of the myocardium, disrupting electrical signal conduction and leading to sudden cardiac death. While the majority of cases are attributed to desmosomal mutations, 1-3% of AC cases involve mutations in non-desmosomal genes, such as LGALS3. This gene is involved in desmosomal stabilization, inflammation, apoptosis, and necrosis, and regulates Wnt/β-catenin pathway expression. Mutations in LGALS3 can detrimentally affect these processes, potentially leading to the development of AC-related phenotypes. The thesis aimed to characterize a zebrafish lgals3a mutant line as an AC model, and investigate LGALS3 role in disease pathogenesis. Additionally, we aimed to identify potential drug candidates and molecular targets for future therapeutic treatments. Our research revealed that lgals3a mutation at the larval stage significantly impacts heart physiology and morphology, causing reduced contractility, bradycardia, and arrhythmia events. Moreover, Transmission Electron Microscopy (TEM) analysis underlined desmosomal destabilization in mutant adult hearts. Additionally, our analysis of inflammation markers showed a high infiltration of inflammatory cells in the cardiac region of lgals3a mutants. AO/EB staining demonstrated elevated number of apoptotic and necrotic cells in mutants. Of note, pharmacological treatment using a Wnt/β-catenin signaling agonist, SB216763, partially rescued the AC phenotype. In conclusion, our results strongly support the utility of the lgals3a mutant line for understanding LGALS3 involvement in AC pathogenesis, offering future perspectives for AC treatment.