Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia

Akitoshi Nakashima,Satoshi Yoneda,Ippei Yasuda,Shi-Bin Cheng,Surendra Sharma,Akemi Yamaki-Ushijima,Atsushi Furuta,Shigeru Saito,Tomoko Shima,Sayaka Tsuda,Mihoko Kawaguchi,Aiko Aoki

doi:10.3390/ijms22052432

Abstract

Aggrephagy is defined as the selective degradation of aggregated proteins by autophagosomes. Protein aggregation in organs and cells has been highlighted as a cause of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. Aggregates could pose a hazard for cell survival. Cells exhibit three main mechanisms against the accumulation of aggregates: protein refolding by upregulation of chaperones, reduction of protein overload by translational inhibition, and protein degradation by the ubiquitin–proteasome and autophagy–lysosome systems. Deletion of autophagy-related genes reportedly contributes to intracellular protein aggregation in vivo. Some proteins recognized in aggregates in preeclamptic placentas include those involved in neurodegenerative diseases. As aggregates are derived both intracellularly and extracellularly, special endocytosis for extracellular aggregates also employs the autophagy machinery. In this review, we discuss how the deficiency of aggrephagy and/or macroautophagy leads to poor placentation, resulting in preeclampsia or fetal growth restriction.

Highlights

Protein aggregation and accumulation in organs have been highlighted as causes of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure
Excessive protein aggregates lead to the disruption of normal functions in trophoblasts, resulting in preeclampsia or fetal growth restriction (FGR)
This suggests that a unique mechanism for protein aggregation exists in placentas with preeclampsia and FGR

Summary

Introduction

Protein aggregation and accumulation in organs have been highlighted as causes of multiple diseases, including neurodegenerative diseases, cardiac failure, and renal failure. In the field of reproduction, the pathological implication of aggregated proteins has been noted, especially preeclampsia, a major cause of maternal and perinatal morbidity and mortality. This syndrome affects both the mother’s and child’s health during pregnancy, as well as in later life. Administration of sFlt and soluble endoglin leads to the development of preeclampsia in pregnant rats [9]. In contrast to these factors, the newly emerging concept of placental protein aggregation is gaining momentum in the pathophysiology of preeclampsia. We discuss the role of protein aggregation in preeclampsia

A Two-Stage to a Four-Stage Model for Placental Development

Role of Autophagy in Placental Development

Aggrephagy in Placentas

Protein Aggregation and ER Stress in Placentas

Findings

Conclusions and Future