ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity

TLDR

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by glucocerebrosidase mutations that lead to glucosylceramide accumulation, with clinical heterogeneity ranging from non‑neurological type 1 to neurological types 2 and 3, and variable disease severity despite identical genotypes. The study aimed to assess glucocerebrosidase protein levels, N‑glycan processing, and intracellular localization in skin fibroblasts from Gaucher patients. Researchers measured glucocerebrosidase abundance, analyzed N‑glycan maturation, and examined subcellular distribution in patient‑derived fibroblasts. Mutant glucocerebrosidase variants exhibit differing levels of ER retention and proteasomal degradation, and this variation correlates with Gaucher disease severity.

Abstract

Gaucher disease (GD), an autosomal recessive disease, is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in the acid β-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients), whereas patients with type 1 GD do not present neurological signs. The disease is heterogeneous even among patients with the same genotype, implicating that a mutation in the glucocerebrosidase gene is required to cause GD but other factors play an important role in the manifestation of the disease. Glucocerebrosidase is a lysosomal enzyme, synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following N-linked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. In this study, we tested glucocerebrosidase protein levels, N-glycans processing and intracellular localization in skin fibroblasts derived from patients with GD. Our results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity.