Cell Models of Genetic Metabolic Diseases

Metabolic diseases constitute a diverse group of disorders affecting the body's metabolism. These conditions vary widely in severity and require accurate identification and diagnosis for optimal patient care. Diseases can be inherited or acquired. One of the rare genetic metabolic diseases is Fabry disease (FD). Fabry disease (FD) is a rare, underdiagnosed lysosomal storage disorder resulting from a deficiency in the alpha-galactosidase A (GLA) enzyme. This enzyme deficiency leads to the accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in various cells and tissues. This accumulation can cause a wide range of symptoms affecting multiple organs. Exosomes, small membrane-bound vesicles secreted by cells, play a crucial role in cellular communication and disease progression, influencing various biological processes, from development and immunity to disease progression. Fabry disease-derived exosomes are no exception. This project explores the impact of FD-derived exosomes on cellular function and disease mechanisms, with a focus on their potential role in affecting organ pathologies and playing as biomarkers for disease progression. By comparing the effects of exosomes from FD patients and healthy controls on different cell models, the study aimed to understand the molecular pathways involved in FD pathogenesis. More specifically, this project investigated the effects of FD-derived exosomes on cellular respiration and autophagy in human umbilical vein endothelial cells (HUVECs) and the HEK293 endothelial-derived human cell line. The effects of FD-derived exosomes on cell viability, respiration, mitochondrial health, and autophagy were assessed using a variety of techniques, including the Seahorse XF Cell Mito Stress Test, MTS test, and classical biochemical assessment (e.g., Western blot analysis of different protein markers). Exosome attachment and uptake were also detected by confocal microscopy. The preliminary results obtained in this study suggest that while FD exosomes did not significantly affect cellular respiration in either cell type, they influenced the expression of the autophagy-related proteins LC3 and p62. These findings suggest a potential role for exosomes in affecting cellular processes in FD in a specific manner, but further research is necessary to fully understand the underlying mechanisms and long-term implications.