Figure 5. β₂-Adrenergic receptor agonists decrease SNCA protein levels and ameliorate lysosomal dysfunction.

(A) Connectivity mapping showing anti-Fabry compounds, with the β₂-adrenergic receptor agonist orciprenaline exhibiting the highest score. (B) Western blots show the expression of SNCA in WT and untreated GLA-KO cells and KO cells treated with 20 μM clenbuterol and 10 μM orciprenaline (n = 6). (C) Western blots depict the expression of LAMP1 and ACTN4 in WT and untreated GLA-KO cells and KO cells treated with aGAL, 20 μM clenbuterol, and combined therapy (n = 6). (D) Lysosomal pH analysis in all conditions demonstrates independent and additive effects of β₂-adrenergic receptor agonist in GLA-KO cells (n = 6). (E) Lysosomal ROS analysis demonstrates independent and additive effects of β₂-adrenergic receptor agonist in GLA-KO cells (n = 6). (F) Schematic summary depicting the overall findings of the study: Fabry podocyte lysosomes are characterized by increased size, pH, and ROS production with subsequently decreased function due to Gb3 and SNCA accumulation. This phenotype can be ameliorated through ERT combined with compounds decreasing SNCA accumulation, like β-receptor agonists. Bar graphs depict standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. One-way ANOVA with Tukey’s multiple-comparison test.