Maturation of Lysosomal α-Galactosidase A and Implications for Fabry Disease

BACKGROUND: Fabry disease is an inherited metabolic disease that is caused by an abnormal accumulation of sphingolipids, including globotriaosylceramide (Gb3), in lysosomes. Patients with Fabry disease have insufficient levels or no total activity of an enzyme called α-galactosidase A, which catalyzes the removal of terminal α-galactose saccharides from substrates such as Gb3. SUMMARY: Because of the monogenetic nature of Fabry disease, the levels of enzyme activity correlate with disease outcome in patients, and thus enable genotype-phenotype predictions in the disease. Although Fabry disease results from reduced α-galactosidase A activity in the lysosome, there are many different molecular mechanisms for the loss of α-galactosidase A activity in Fabry disease patients, so it is of utmost importance to understand the journey and maturation of α-galactosidase A inside the cell. The proper synthesis of α-galactosidase A requires many steps, including the folding of the polypeptide, posttranslational modifications, trafficking of the enzyme to the lysosome, and substrate binding. Furthermore, researchers and clinicians benefit from extensive clinical data, with over 1,000 different mutations identified in patients, many of which are investigated by researchers. Finally, the availability of a pharmacological chaperone, which enhances the enzymatic activity of many α-galactosidase A variants, allows us to understand the biology better. KEY MESSAGES: This review will focus on the molecular steps that must be precisely orchestrated to properly synthesize the α-galactosidase A enzyme, and how failures in different maturation steps of α-galactosidase A lead to Fabry disease. We also describe how different treatment options address the loss of α-galactosidase A activity in the lysosome of patients.