Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia

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.

Keywords: aggrephagy; aggresome; autophagy; endoplasmic reticulum stress; inflammation; placenta; preeclampsia; pregnancy; protein aggregation; transthyretin.

Figure 1

Autophagy cascade. Microtubule-associated protein 1 light chain 3 (LC3-I), which is generated from pro-LC3-I by Atg4B, is converted to LC3-II by Atg7 and Atg4B. Atg4B also mediates the conversion of LC3-II to LC3-I. An isolation membrane is elongated with LC3-II and Atg5-Atg12-Atg16L complex. The isolation membranes are closed, resulting in the autophagosome. Subsequently, the autophagosome fuses with lysosome, in which LAMP1 is expressed in the membrane, and digests the contents of the inner membrane. Lysosomes are also generated from the autolysosome by a recycling of protolysosomal membrane components.

Figure 2

Aggregates in the Atg7 conditional knockout placenta. Atg7 deficiency in trophoblasts reduces the area of the spongiotrophoblast layer, compared with the control. Aggregated proteins accumulate in the area accompanied with SQSTM1 deposition, resulting in the increase of apoptosis.

Figure 3

Transfer of aggregated proteins to aggresome in MTOC. Misfolded proteins build the cytotoxic aggregated protein. The aggregated protein, which is K63-polyubiquitinated, is trapped with HDAC6. The HDAC6 complex is transferred to the microtubule organizing center (MTOC) via dynein, resulting in aggresome. The autophagic adaptor proteins, SQSTM1 and ALFY, bind to aggresome to attract autophagosome membrane.