Increased glucocerebrosidase expression and activity in preeclamptic placenta

Abstract Introduction Lysosomal glucosidase beta acid (GBA) deficiency is inherent to Gaucher disease, Parkinsonism and Lewy-body dementia. Increased GBA expression has never been associated with human disease. We describe increased GBA expression and activity in placenta from preeclamptic pregnanci...

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Bibliographic Details
Published in:Placenta (Eastbourne) 2015-02, Vol.36 (2), p.160-169
Main Authors: Jebbink, J.M, Boot, R.G, Keijser, R, Moerland, P.D, Aten, J, Veenboer, G.J.M, van Wely, M, Buimer, M, Ver Loren van Themaat, E, Aerts, J.M.F.G, van der Post, J.A.M, Afink, G.B, Ris-Stalpers, C
Format: Article
Language:English
Subjects:
BMP4
Ceramides - metabolism
Enzyme Activation
Expression
Female
GBA
Gene Expression Regulation, Enzymologic
Glucocerebrosidase
Glucosylceramidase - genetics
Glucosylceramidase - metabolism
Glucosylceramides - metabolism
HEK293 Cells
Humans
Infant, Newborn
Internal Medicine
Male
Obstetrics and Gynecology
Placenta
Placenta - enzymology
Placenta - metabolism
Pre-Eclampsia - enzymology
Pre-Eclampsia - genetics
Pre-Eclampsia - metabolism
Preeclampsia
Pregnancy
Up-Regulation - genetics
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Summary:Abstract Introduction Lysosomal glucosidase beta acid (GBA) deficiency is inherent to Gaucher disease, Parkinsonism and Lewy-body dementia. Increased GBA expression has never been associated with human disease. We describe increased GBA expression and activity in placenta from preeclamptic pregnancies. Methods 112 placenta biopsies were available for qPCR, analysis of GBA gene expression and activity. Microanalysis was performed on 20 placenta samples. Alternatively spliced placental GBA transcripts were cloned, expressed in HEK293 cells and analyzed by Western blot and activity assay. Results GBA is expressed in the syncytiotrophoblast layer of human placenta already at 5 weeks of gestation. We identified five novel GBA transcripts in placenta that enzymatically inactive when expressed in HEK293 cells. Both GBA RNA expression and enzymatic activity are upregulated in preeclamptic placenta. Microarray analysis of 20 placenta tissues identified 158 genes co-regulating with GBA expression and gene enrichment analysis highlights lysosomal function. In our micro-array data GBA expression does not correlate with FLT1 expression, currently the most powerful marker for preeclampsia. There are 89 transcripts that are negatively correlated with GBA expression of which BMP4 and TFEB are interesting as they are essential to early placenta function. Discussion Although very speculative, we hypothesize that increased GBA expression might relate to placentation through decreased BMP4 signaling or vascularization through downregulation of TFEB . Ceramide, the product of hydrolysis of glucosylceramide by GBA and involved in the regulation of cell differentiation, survival and apoptosis, is another putative candidate linking increased GBA activity to preeclampsia. Both pathways merit further investigation.
ISSN:0143-4004
1532-3102
DOI:10.1016/j.placenta.2014.12.001