A possible structural basis behind the pathogenic role of apolipoprotein E hereditary mutations associated with lipoprotein glomerulopathy
Abstract
Single amino acid mutations in apolipoprotein E (apoE) have been associated with the development of the rare kidney disease lipoprotein glomerulopathy (LPG). Although the genetic linkage to disease development is well established, the mechanism of pathogenesis is largely unknown, limiting therapeutic insight. Here, we summarize current knowledge in the field and focus on the possible effects of LPG-associated mutations on the structure of apoE. Recent findings have suggested that mutation-induced folding perturbations in apoE lead to structural destabilization and aggregation, effects that may underlie lipoprotein thrombi accumulation in the glomerulus, a hallmark of LPG. The recognition that structural destabilization may underlie the association between apoE mutations and LPG can be key for development of new innovative treatments for this rare disease.
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Mutated apoE has been proposed as a factor outside the kidney crucial for LPG pathogenesis because LPG is related to inherited apoE gene mutations acting dominantly with incomplete penetrance.
“One such factor has been proposed to be mutated apoE, because LPG has been related with inherited mutations within the apoE gene that act in a dominant way but with incomplete penetrance (1,2,5,6).”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [6]
The majority of LPG-associated apoE mutations are located in the helical N-terminal domain of apoE.
“The majority of LPG-associated apoE mutations are located in the helical N-terminal domain of the molecule (5,6).”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [6]
Most LPG patients have been reported to present elevated plasma apoE levels, while normalization or reduction of apoE levels following various treatments results in remission or improvement of the disease.
“Most of the LPG patients have been reported to present elevated plasma apoE levels (5, 6, 23-25), while it has been observed that normalization or reduction of apoE levels following various treatments (e.g., lipid-lowering treatments with fenofibrate or protein A immunoadsorption) result in remission or improvement of the disease (24,25,47).”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [6]
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Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease
Marais, A. D. (2019) · Pathology · doi:10.1016/j.pathol.2018.11.002 · Cited by 382 · see citing works
Katsarou, M., Stratikos, E., & Chroni, A. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m088732 · Cited by 22 · see citing works
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- Authors
- Stratikos, E., & Chroni, A.
- Affiliations
- National Centre of Scientific Research "Demokritos" (GR)
- Corresponding author
- Stratikos, Efstratios
- Venue
- Clinical and Experimental Nephrology
- Published
- 2013-10-23
- Volume
- 18
- Issue
- 2
- Pages
- 225-229
- ISSN
- 1342-1751 (ISSN-L)
- 1437-7799
- OpenAlex
- W2032796952
- Cited by
- 5
- References
- 7
- Citations by year
- 2019: 1 · 2018: 3 · 2017: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Clinical and Experimental Nephrology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, lipoprotein glomerulopathy, single amino acid mutations, protein structural destabilization, protein aggregation, protein folding, glomerular disease pathogenesis, rare kidney disease
- MeSH terms
- Apolipoproteins E, Humans, Kidney Diseases, Kidney Glomerulus, Protein Conformation, Receptors, LDL, Thermodynamics, Protein Unfolding
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