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Cholesterol and Sphingomyelin Uniquely Alter the Rate of Transthyretin Aggregation and Decrease the Toxicity of
Abid Ali1, Kiryl Zhaliazka1, Tianyi Dou1
1Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
The Journal of Physical Chemistry Letters
|November 30, 2023
Summary
Cholesterol accelerates transthyretin (TTR) aggregation, while phosphatidylcholine and sphingomyelin inhibit it. These lipids alter TTR fibril structure and toxicity, suggesting a role in transthyretin amyloidosis development.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Transthyretin (TTR) is a protein known to aggregate into toxic forms.
- TTR interacts with biomolecules, including lipids on red blood cell membranes.
- The influence of these membrane components on TTR aggregation is not well understood.
Purpose of the Study:
- To investigate how phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Cho) affect TTR aggregation rates.
- To determine if these lipids modify the structure and toxicity of TTR aggregates.
Main Methods:
- In vitro studies examining TTR aggregation kinetics in the presence of PC, SM, and Cho.
- Analysis of the morphology and secondary structure of TTR fibrils formed with varying lipid compositions.
Main Results:
- Phosphatidylcholine (PC) and sphingomyelin (SM) were found to inhibit TTR aggregation.
- Cholesterol (Cho) significantly accelerated the rate of TTR aggregation.
- Lipid-induced TTR aggregates exhibited altered morphology and secondary structure, impacting their toxicity.
Conclusions:
- Interactions with red blood cell membrane lipids differentially modulate TTR aggregation.
- Cholesterol's accelerating effect and lipid-mediated structural changes suggest a mechanism for TTR aggregation in transthyretin amyloidosis.
- These findings highlight the potential role of cell membrane components in amyloid disease pathogenesis.
