title: Increased glucocerebrosidase expression and activity in preeclamptic placenta.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics, Academic Medical Center, Amsterdam, The Netherlands; Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: j.m.jebbink@amc.uva.nl.
authors.forename: J M
authors.initials: JM
authors.lastname: Jebbink
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: R G
authors.initials: RG
authors.lastname: Boot
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Keijser
authors.affiliation: Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: P D
authors.initials: PD
authors.lastname: Moerland
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Aten
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: G J M
authors.initials: GJ
authors.lastname: Veenboer
authors.affiliation: Center for Reproductive Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van Wely
authors.affiliation: Department of Obstetrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Buimer
authors.affiliation: Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Ver Loren van Themaat
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J M F G
authors.initials: JM
authors.lastname: Aerts
authors.affiliation: Department of Obstetrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J A M
authors.initials: JA
authors.lastname: van der Post
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: G B
authors.initials: GB
authors.lastname: Afink
authors.affiliation: Department of Obstetrics, Academic Medical Center, Amsterdam, The Netherlands; Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Ris-Stalpers
mesh_terms: D002518:Ceramides / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism*; D005963:Glucosylceramides / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010920:Placenta / Q000201:enzymology / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D015854:Up-Regulation / Q000235:genetics
chemical_list: D002518:Ceramides; D005963:Glucosylceramides; D005962:Glucosylceramidase
keywords: BMP4; Expression; GBA; Glucocerebrosidase; Placenta; Preeclampsia