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
Department of Obstetrics, Academic Medical Center, Amsterdam, The Netherlands; Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
Placenta. 2015 Feb;36(2):160-9. doi: 10.1016/j.placenta.2014.12.001. Epub 2014 Dec 13.
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.
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.
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.
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.
溶酶体葡糖苷酶β酸性（GBA）缺乏是戈谢病、帕金森综合征和路易体痴呆的内在特征。GBA表达增加从未与人类疾病相关联。我们描述了子痫前期妊娠胎盘GBA表达和活性增加的情况。
112份胎盘活检样本用于qPCR、GBA基因表达和活性分析。对20份胎盘样本进行了微量分析。对胎盘GBA转录本的可变剪接体进行克隆，在HEK293细胞中表达，并通过蛋白质印迹和活性测定进行分析。
GBA在妊娠5周时就已在人胎盘的合体滋养层中表达。我们在胎盘中鉴定出5种新的GBA转录本，它们在HEK293细胞中表达时无酶活性。子痫前期胎盘中GBA RNA表达和酶活性均上调。对20份胎盘组织的微阵列分析确定了158个与GBA表达共同调控的基因，基因富集分析突出了溶酶体功能。在我们的微阵列数据中，GBA表达与FLT1表达不相关，FLT1目前是子痫前期最有力的标志物。有89个转录本与GBA表达呈负相关，其中BMP4和TFEB很有意思，因为它们对早期胎盘功能至关重要。
尽管极具推测性，但我们假设GBA表达增加可能通过降低BMP4信号传导与胎盘形成有关，或者通过下调TFEB与血管形成有关。神经酰胺是GBA水解葡萄糖神经酰胺的产物，参与细胞分化、存活和凋亡的调节，是将GBA活性增加与子痫前期联系起来的另一个假定候选物。这两条途径都值得进一步研究。
