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

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. Clinical findings in affected males revealed a milder clinical course with ~15% residual AGAL activity and borderline plasma lyso-Gb3Cer levels. Kidney biopsies did not show lysosomal storage. Laboratory investigations documented intracellular retention of mutated AGAL with resulting endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which were alleviated with BRD4780, a small molecule clearing misfolded proteins from the early secretory compartment. We observed similar findings of ER stress and UPR with several other classic and non-classic FD missense AGAL variants. 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.