AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Abstract

Background Classic Fabry disease (FD) is caused by GLA mutations that result in enzymatic deficiency of alpha-galactosidase A (AGAL), lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic later-onset FD, patients have some preserved AGAL activity and a milder disease course, though female carriers may also be affected. While FD pathogenesis has been mostly attributed to catalytic deficiency of mutated AGAL, lysosomal storage and impairment of lysosomal functions, other pathogenic factors may be important, especially in non-classic later-onset FD. Methods We characterized the clinical, biochemical, genetic, molecular, cellular and organ pathology correlates of the p.L394P AGAL variant that was identified in six individuals with end-stage kidney disease by the Czech national screening program for FD and by further screening of 25 family members. Results Clinical findings revealed a milder clinical course with ~15% residual AGAL activity. Laboratory investigations documented intracellular retention of mutated AGAL with resulting ER stress and the unfolded protein response (UPR). Kidney biopsies did not show lysosomal storage. We observed similar findings of ER stress and UPR with several other classic and non-classic FD missense GLA variants. Conclusions We identified defective proteostasis of mutated AGAL resulting in chronic ER stress and UPR of AGAL expressing cells (hereafter referred to as AGALopathy) as an important contributor to FD pathogenesis. These findings provide insight into non-classic later-onset FD and may better explain clinical manifestations with implications for pathogenesis, clinical characterization and treatment of all FD forms.

Gene Expression Analysis in gla-Mutant Zebrafish Reveals Enhanced Ca2+ Signaling Similar to Fabry Disease

“…A possible explanation to this contradiction is that in these studies, lysosomal dysregulation is attributed to the Gb3 accumulation while in our study we highlight the Gb3-independent effect in a complete Gb3-free environment. We therefore suggest that the effect seen in our study is triggered through alternative pathways, for example the UPR which has recently been reported in FD [23,24].…”

“…It is worth mentioning that in addition to the injuries caused by the Gb3 accumulation in FD, other injuries or reactions resulting from the mutant protein can also be attributed to the disease cause, for example the unfolded protein response (UPR) [22]. Recently, it has been shown that such response can cause endoplasmic reticulum stress, mitochondrial stress and lysosomal stress before the Gb3 accumulation effect [23,24].…”

Genetic variants of unknown significance in alpha‐galactosidase A: Cellular delineation from Fabry disease

“…Incorrect trafficking of the misfolded GLA enzyme is proposed as an alternative pathophysiological mechanism that may cause ER stress. 30,31 Using colocalization analysis, we show normal trafficking of GLA to the lysosomes in HDF carrying the investigated genetic variants compared to controls. While limited to a single in vitro model and to variants without known mistrafficking, this experiment provides a proof-of-principle for the assessment of GLA dynamics.…”