Human Molecular Genetics Advance Access published online on February 3, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp061
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No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease
1 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel 2 Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine and the Strategic, Research Center for Stem Cell Biology and Cell Therapy, Lund University, BMC A12, 221 84 Lund, Sweden
* Address correspondence to A.H. Futerman, Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. Fax; +(972)-8-9344112: Tel; +(972)-8-9342704: e-mail: tony.futerman{at}weizmann.ac.il
Received January 7, 2009; Revised February 2, 2009; Accepted February 2, 2009
Gaucher disease, the most common lysosomal storage disorder (LSD), is caused by defects in the activity of the lysosomal enzyme, glucocerebrosidase (GlcCerase), resulting in intracellular accumulation of glucosylceramide (GlcCer). Neuronopathic forms, which comprise only a small percent of Gaucher disease patients, are characterized by neurological impairment and neuronal cell death. Little is known about the pathways leading from GlcCer accumulation to neuronal death or dysfunction but defective calcium homeostasis appears to be one of the pathways involved. Recently, endoplasmic reticulum (ER) stress together with activation of the unfolded protein response (UPR) has been suggested to play a key role in cell death in neuronopathic forms of Gaucher disease, and moreover, the UPR was proposed to be a common mediator for apoptosis in LSDs (Wei et al. (2008) Hum. Mol. Genetics 17, 469-477). We now systematically examine whether the UPR is activated in neuronal forms of Gaucher disease using a selection of neuronal disease models and a combination of western blotting and semi-quantitative and quantitative real time PCR. We do not find any changes in either protein or mRNA levels of a number of typical UPR markers including BiP, CHOP, XBP1, Herp and GRP58, in either cultured Gaucher neurons or astrocytes, or in brain regions from mouse models, even at late symptomatic stages. We conclude that the proposition that the UPR is a common mediator for apoptosis in all neurodegenerative LSDs needs to be re-evaluated.