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Abrupt aggregation of misfolded proteins is the underlying molecular cause of numerous severe pathologies including Alzheimer's and Parkinson's diseases. Protein aggregation yields small oligomers that can later propagate into amyloid fibrils, β‐sheet‐rich structures with a variety of topologies. A growing body of evidence suggests that lipids play an important role in abrupt aggregation of misfolded proteins. In this study, we investigate the roles of length and saturation of fatty acids (FAs) in phosphatidylserine (PS), an anionic lipid that is responsible for the recognition of apoptotic cells by macrophages, in lysozyme aggregation. We found that both the length and saturation of FAs in PS contribute to the aggregation rate of insulin. PS with 14‐carbon‐long FAs (14:0) enabled a much stronger acceleration of protein aggregation compared to PS with 18‐carbon‐long FAs (18:0). Our results demonstrate that the presence of double bonds in FAs accelerated the rate of insulin aggregation relative to PS with fully saturated FAs. Biophysical methods revealed morphological and structural differences in lysozyme aggregates grown in the presence of PS with varying lengths and FA saturation. We also found that such aggregates exerted diverse cell toxicities. These results demonstrate that the length and saturation of FAs in PS can uniquely alter the stability of misfolded proteins on lipid membranes. [ABSTRACT FROM AUTHOR]

The progressive aggregation of misfolded proteins is the underlying molecular cause of numerous pathologies including Parkinson's disease and injection and transthyretin amyloidosis. A growing body of evidence indicates that protein deposits detected in organs and tissues of patients diagnosed with such pathologies contain fragments of lipid membranes. In vitro experiments also showed that lipid membranes could strongly change the aggregation rate of amyloidogenic proteins, as well as alter the secondary structure and toxicity of oligomers and fibrils formed in their presence. In this review, the effect of large unilamellar vesicles (LUVs) composed of zwitterionic and anionic phospholipids on the aggregation rate of insulin, lysozyme, transthyretin (TTR) and α- synuclein (α-syn) will be discussed. The manuscript will also critically review the most recent findings on the lipid-induced changes in the secondary structure of protein oligomers and fibrils, as well as reveal the extent to which lipids could alter the toxicity of protein aggregates formed in their presence. [Display omitted] • The review discusses the effect of zwitterionic and anionic phospholipids on the aggregation of amyloidogenic proteins. • Recent findings on the lipid-induced changes in the secondary structure of protein oligomers and fibrils are reviewed. • Future perspectives of amyloid biology and therapeutic approaches against amyloidogenic pathologies are summarized. • A relationshpi between the secondary structure of amyloids and their toxicity is discussed. [ABSTRACT FROM AUTHOR]

Transthyretin amyloidosis is a severe pathology characterized by the progressive accumulation of transthyretin (TTR) in various organs and tissues. This highly conserved through vertebrate evolution protein transports thyroid hormone thyroxine. In our bodies, TTR can interact with a large number of molecules, including ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) that are broadly used as food supplies. In this study, we investigated the effect of ω-3 and ω-6 PUFAs, as well as their fully saturated analog, on TTR aggregation. Our results showed that both ω-3 and ω-6 PUFAs strongly decreased the rate of TTR aggregation. We also found that in the presence of PUFAs, TTR formed morphologically different fibrils compared to the lipid-free environment. Nano-Infrared imaging revealed that these fibrils had drastically different secondary structures compared to the secondary structure of TTR aggregates formed in the PUFAs-free environment. Furthermore, TTR fibrils formed in the presence of ω-3 and ω-6 PUFAs exerted significantly lower cell toxicity compared to the fibrils formed in the absence of fatty acids. [ABSTRACT FROM AUTHOR]