Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jan 26;29(3):610.
doi: 10.3390/molecules29030610.

Protein Misfolding in Pregnancy: Current Insights, Potential Mechanisms, and Implications for the Pathogenesis of Preeclampsia

Bani Medegan Fagla  1 , Irina Alexandra Buhimschi  1
Affiliations
Review

Protein Misfolding in Pregnancy: Current Insights, Potential Mechanisms, and Implications for the Pathogenesis of Preeclampsia

Bani Medegan Fagla et al. Molecules. .

Abstract

Protein misfolding disorders are a group of diseases characterized by supra-physiologic accumulation and aggregation of pathogenic proteoforms resulting from improper protein folding and/or insufficiency in clearance mechanisms. Although these processes have been historically linked to neurodegenerative disorders, such as Alzheimer's disease, evidence linking protein misfolding to other pathologies continues to emerge. Indeed, the deposition of toxic protein aggregates in the form of oligomers or large amyloid fibrils has been linked to type 2 diabetes, various types of cancer, and, in more recent years, to preeclampsia, a life-threatening pregnancy-specific disorder. While extensive physiological mechanisms are in place to maintain proteostasis, processes, such as aging, genetic factors, or environmental stress in the form of hypoxia, nutrient deprivation or xenobiotic exposures can induce failure in these systems. As such, pregnancy, a natural physical state that already places the maternal body under significant physiological stress, creates an environment with a lower threshold for aberrant aggregation. In this review, we set out to discuss current evidence of protein misfolding in pregnancy and potential mechanisms supporting a key role for this process in preeclampsia pathogenesis. Improving our understanding of this emerging pathophysiological process in preeclampsia can lead to vital discoveries that can be harnessed to create better diagnoses and treatment modalities for the disorder.

Keywords: Alzheimer’s disease; amyloid-β; preeclampsia; protein misfolding; tau; transthyretin.

PubMed Disclaimer

Conflict of interest statement

IAB is named as the co-inventor on patents claiming protein misfolding, congophilia, and conformational-dependent immunoreactivity as diagnostic and therapeutic targets for preeclampsia. The patents have been licensed for commercialization to private entities. BMF has no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Diagram of pathophysiological processes described in the central hypothesis of PE pathogenesis, illustrating multifactorial etiologies that could trigger the widely accepted canonical pathway. Canonical mechanisms involved in PE pathogenesis and their progression to PE symptomatology are highlighted in red. Upward arrows indicate the pathological processes and vascular markers that increase in PE, while downward arrows represent markers that are known to decrease. A handful of other alternate or complementary etiological factors that have been proposed to contribute to these central mechanisms are shown in grey (immune maladaptation, genetic factors, cardiovascular maladaptation, environmental factors); and orange for protein misfolding, which this review will focus on. Created with BioRender.com, accessed on 18 December 2023.
Figure 2
Figure 2
Illustrative diagram of native protein structure formation and amyloid fibril formation pathways. Canonical processes are indicated by full arrows, while alternate pathways are indicated by dashed arrows. Black arrows were used for processes of normal protein folding, while grey arrows were used to indicate fibrillation mechanisms. Created with BioRender.com, accessed on 20 January 2024.
Figure 3
Figure 3
Schematic of the protein aggregation cascade and their potential multisystemic effects leading to or resulting from PE onset. Validated processes are shown by full arrows, while proposed potential mechanisms are indicated by dashed arrows. Created with BioRender.com, accessed on 20 January 2024.
Figure 4
Figure 4
Shared proteins are found in AD-associated brain amyloid plaques and PE-associated placental and urine protein aggregates. Created with BioRender.com, accessed on 20 January 2024.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Labbadia J., Morimoto R.I. The Biology of Proteostasis in Aging and Disease. Annu. Rev. Biochem. 2015;84:435–464. doi: 10.1146/annurev-biochem-060614-033955. - DOI - PMC - PubMed
    1. Bradbury J. Chaperones: Keeping a Close Eye on Protein Folding. Lancet. 2003;361:1194–1195. doi: 10.1016/S0140-6736(03)12975-3. - DOI - PubMed
    1. Chaudhuri T.K., Paul S. Protein-Misfolding Diseases and Chaperone-Based Therapeutic Approaches. FEBS J. 2006;273:1331–1349. doi: 10.1111/j.1742-4658.2006.05181.x. - DOI - PubMed
    1. Powers E.T., Morimoto R.I., Dillin A., Kelly J.W., Balch W.E. Biological and Chemical Approaches to Diseases of Proteostasis Deficiency. Annu. Rev. Biochem. 2009;78:959–991. doi: 10.1146/annurev.biochem.052308.114844. - DOI - PubMed
    1. Williams D. Pregnancy: A Stress Test for Life. Curr. Opin. Obstet. Gynecol. 2003;15:465. doi: 10.1097/00001703-200312000-00002. - DOI - PubMed