Protective effect of recombinant human erythropoietin in type II Gaucher disease patient cells by scavenging endoplasmic reticulum stress

Abstract

Gaucher disease (GD) is an inherited disorder characterized by excessive accumulation of glucocerebroside in cells due to a non-functional glucocerebrosidase that is linked to programmed cell death pathways. Although clinical manifestations vary, type II GD is the most severe phenotype characterized by endoplasmic reticulum (ER) stress, neurological dysfunction, and anemia. Recombinant human erythropoietin (EPO) has been very popular for treating renal anemia and recently was shown to have extra-hematopoietic effects including neuroprotective properties. EPO's hematopoietic and neuroprotective effects prompted us to test EPO's beneficial action on type II GD patient cells. Initially, to examine the responsiveness of type II GD cells to EPO, the expression of the EPO receptor was determined at mRNA and protein levels. EPO effects on signaling pathways and ER stress in GD cells were also investigated. Finally, the proliferative effect of EPO on GD cells was verified. We found that EPO stimulated signaling pathways, enhanced the expression of glucocerebrosidase, reduced ER stress marker protein levels, and enhanced the proliferation rate of type II GD patient cells. This novel approach involving a beneficial role of EPO in GD should provide insights into new concepts for treating GD.