Impact of ER stress and the unfolded protein response on Fabry disease

Fabry disease (FD) is a lysosomal storage disorder caused by pathogenic missense and nonsense variants in the α-galactosidase A (GLA) gene, leading to absent or reduced enzyme activity. The resulting lysosomal accumulation of the substrate globotriaosylceramide leads to progressive renal failure, cardiomyopathy with (malignant) cardiac arrhythmias and progressive heart failure as well as recurrent strokes, which significantly limits the life expectancy of patients affected with FD. There is increasing evidence that pathogenic GLA missense variants as well as formally benign GLA variants can cause retention in the endoplasmic reticulum (ER), resulting in ER stress, which in turn triggers an unfolded protein response (UPR) leading to cellular dysregulation including inflammation, irreversible cell damage, and apoptosis. This review aims to provide an update on the pathogenetic significance of ER stress and UPR in FD, current treatment options, including pharmaceutical and chemical chaperones, and an outlook on current research and future treatment options in FD.