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The following is a summary of “Misprocessing of Alpha-Galactosidase A, Endoplasmic Reticulum Stress, and the Unfolded Protein Response,” published in the November 2024 issue of Nephrology by Živná et al. 

Fabry disease arises from GLA mutations leading to alpha-galactosidase A deficiency and lysosomal dysfunction. Non-classic cases show milder symptoms with some preserved enzymatic activity. 

Researchers conducted a retrospective study on Fabry disease and found endoplasmic reticulum stress contributing to its pathogenesis. 

They analyzed 30 individuals, including 6 with kidney failure and 24 family members, using genetic, clinical, biochemical, and molecular methods to characterize the p.L394P alpha-galactosidase A variant. 

The results showed a milder male disease with ~15% residual enzyme activity, normal plasma lyso-globotriaosylceramide levels, and no lysosomal storage in 4 kidney biopsies. Intracellular retention caused endoplasmic reticulum stress, alleviated by BRD4780. Similar findings were noted in 5 kidney biopsies with other Fabry variants, highlighting a shared pathogenic mechanism. 

They found defective proteostasis of mutated alpha-galactosidase A causing chronic endoplasmic reticulum stress and unfolded protein response. They concluded this as a key contributor to Fabry disease pathogenesis. 

Source: journals.lww.com/jasn/abstract/9900/misprocessing_of_alpha_galactosidase_a,.483.aspx