Exosome Secretion and Cellular Signaling Change in a Fabry Disease Cell Model Induced by Gene-silencing

Fabry disease (FD) is caused by α-galactosidase A (AGA) deficiency, which ultimately leads to the intracellular accumulation of globotriaosylceramide (Gb3). Exosomes play a role in maintaining cellular homeostasis by clearing damaged or toxic materials, including proteins. In the process of excessive accumulation of intracellular Gb3 in Fabry disease, it may be suggested that exosomal secretion of Gb3 increases to preserve cell homeostasis. This study sought to determine how exosomal secretion and cell signaling change in an FD cell model produced by gene silencing.

HEK293T cells were transfected with plasmids carrying shRNA against the GLA gene to produce the FD cell model. A recombinant AGA, agalsidase-beta, was used to evaluate the effect of enzyme replacement therapy (ERT) on exosomal secretion and cell signaling.

Exosome secretion was significantly increased in the Fabry disease cell model compared to the control vector cell model, and significantly decreased after agalsidase-beta treatment. The FD cell model showed higher reactive oxygen species (ROS) production and p53 protein expression compared to the control vector cell model.

Increased exosomal secretion in Fabry disease may be a cellular mechanism to avoid excessive and cytotoxic accumulation of Gb3 in lysosomes through intracellular signaling, including increased p53 expression.