UPR activation and CHOP mediated induction of GBA1 transcription in Gaucher disease

Abstract

Chronic presence of mutant, misfolded proteins in the endoplasmic reticulum (ER) initiates ER stress and induces the Unfolded Protein Response (UPR).In Gaucher disease (GD), resulting from mutations in the GBA1 gene, encoding lysosomal acid β-glucocerebrosidase (GCase), a certain fraction of the mutant variants is retained in the ER and activates the UPR. We have previously shown UPR activation in GD derived fibroblasts, in fibroblasts that derived from carriers of GD mutations and in Drosophila models of carriers of GD mutations.In the present work we extended our studies to include a large collection of fibroblasts, EBV-transformed B-cells and white blood cells (WBCs) that derived from GD patients.The results showed UPR activation in all tested cells. They also indicated that transcription of the GBA1 gene is upregulated through activation of the UPR-induced CHOP transcription factor. Transcription of the MAN2B gene, encoding alpha-mannosidase and of the ACP gene, encoding acid phosphatase was also elevated presumably through CHOP activation.Our results highlight the existence of chronic stress in GD derived cells due to the presence of ER-retained mutant GCase, which leads to upregulation of GBA1 expression.