Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia.

Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia. Autophagy. 2019 Dec 20;: Authors: Nakashima A, Cheng SB, Ikawa M, Yoshimori T, Huber WJ, Menon R, Huang Z, Fierce J, Padbury JF, Sadovsky Y, Saito S, Sharma S Abstract The etiology of preeclampsia (PE), a serious pregnancy complication, remains an enigma. We have demonstrated that proteinopathy, a pathologic feature of neurodegenerative diseases, is a key observation in the placenta and serum from PE patients. We hypothesize that the macroautophagy/autophagy machinery that mediates degradation of aggregated proteins and damaged organelles is impaired in PE. Here, we show that TFEB (transcription factor EB), a master transcriptional regulator of lysosomal biogenesis, and its regulated proteins, LAMP1, LAMP2, and CTSD (cathepsin D), were dysregulated in the placenta from early and late onset PE deliveries. Primary human trophoblasts and immortalized extravillous trophoblasts (EVTs) showed reduced TFEB expression and nuclear translocation as well as lysosomal protein content in response to hypoxia. Hypoxia-exposed trophoblasts also showed decreased PPP3/calcineurin phosphatase activity and increased XPO1/CRM1 (exportin 1), events that inhibit TFEB nuclear translocation. These proteins were also dysregulated in the PE placenta. These results are supported by observed lysosomal ultrastructural defects with decreased number of autolysosomes in hypoxia...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research