271-POS

Abstract

Objectives In our quest to contribute to the definition of a molecular preeclamptic signature we encountered acid beta glucosidase (GBA, encoding for the enzyme glucocerebrosidase) as a gene that is up regulated in preeclamptic placentas. GBA deficiency causes Gaucher’s disease, a lysosomal storage disease. GBA hydrolyzes glucosylceramide to free glucose and ceramide. Ceramide is a bioactive signaling molecule involved in the regulation of cell movement, differentiation, survival and apoptosis. Purified GBA from placenta extracts was used to treat Gaucher patients with enzyme replacement therapy before the recombinant protein became available. The reason for the abundant expression in placenta and its role in the (patho) physiology of pregnancy is a complete enigma. Methods We used multiple molecular techniques such as real time polymerase chain reaction, a lysosomal enzyme activity assay, 5′ race to detect alternatively spliced variants, transfection of different variants in HEK-293 cells and Western blot analysis, in situ hybridization and immunofluorescence assays to determine cellular localization and micro-array analysis to determine correlation of GBA expression to expression levels of other genes in placenta. Results GBA is up regulated and there is increased lysosomal activity in the preeclamptic placenta. In placenta multiple variants are present but only the full-length GBA protein possesses classical lysosomal activity indicating its role in the lysosomal pathway in placenta. GBA is located in the syncytiotrophoblast layer of the placenta and immunofluorescence is suggestive of lysosomal localization. 158 genes correlate either positively or negatively with GBA expression. Gene enrichment analysis confirms the lysosomal pathway in placenta. Conclusions The increased levels of GBA are most probably a result of the increased cell turnover in the preeclamptic placenta. However since we expect higher levels of ceramide in those cases it may also put ceramide forward as a novel etiological factor in the pathophysiology of preeclampsia. Disclosures J.M. Jebbink: None. R.G. Boot: None. R. Keijser: None. P.D. Moerland: None. J. Aten: None. G.J. Veenboer: None. M. van Wely: None. M. Buimer: None. E. Ver Loren van Themaat: None. J.M. Aerts: None. J.A. van der Post: None. G.B. Afink: None. C. Ris-Stalpers: None.