Fatty Acids Reverse the Supramolecular Chirality of Insulin Fibrils

Holman, Aidan P.; Quinn, Kimberly A.; Kumar, Rakesh; Kmiecik, Sebastian; Ali, Abid; Kurouski, Dmitry

doi:10.1021/acs.jpclett.3c01527

Cited by 9 publications

(12 citation statements)

References 30 publications

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“…Specifically, all ω-3 LCPUFAs strongly accelerated protein aggregation, whereas ω-6 and other LCUFAs and LCPUFAs could or could not exert similar effects on the rate of protein aggregation. Using molecular docking simulations, Holman and co-workers recently showed that the ω-3 C18:3 LCPUFA has much lower binding energy to insulin compared to C22:6, C20:5, C16:1, C18:0, and C18:1 LCPUFAs and LCUFAs . Although no calculations were made for C18:4 (ω-3 LCPUFAs) and C18:2 (ω-6 LCPUFAs), these results indicate that observed differences in the rate of protein aggregation could be linked to the more favorable interaction of ω-3 LCPUFAs with insulin.…”

Section: Resultsmentioning

confidence: 99%

“…Using molecular docking simulations, Holman and co-workers recently showed that the ω-3 C18:3 LCPUFA has much lower binding energy to insulin compared to C22:6, C20:5, C16:1, C18:0, and C18:1 LCPUFAs and LCUFAs. 29 Although no calculations were made for C18:4 (ω-3 LCPUFAs) and C18:2 (ω-6 LCPUFAs), these results indicate that observed differences in the rate of protein aggregation could be linked to the more favorable interaction of ω-3 LCPUFAs with insulin. Microscopic examination of protein aggregates formed in the presence of LCUFAs and LCPUFAs revealed the presence of fibril species that had similar dimensions to the protein aggregates formed in the UFA-free environment.…”

Section: Morphological Examination Of Insulin Aggregates Grown In The...mentioning

confidence: 90%

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Long-Chain Polyunsaturated Fatty Acids Accelerate the Rate of Insulin Aggregation and Enhance Toxicity of Insulin Aggregates

Hoover,

Lynn,

Zhaliazka

et al. 2023

ACS Chem. Neurosci.

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Long-chain polyunsaturated fatty acids (LCPUFAs) are essential components of a human diet. These molecules are critically important for cognitive attention and memory, mood states, coronary circulation, and cirrhosis. However, recently reported findings demonstrated that docosahexaenoic (DHA) and arachidonic acids (ARA), ω-3 and ω-6 LCPUFAs, accelerated the aggregation rates of insulin and α-synuclein, proteins that are directly linked to diabetes type 2 and Parkinson's disease, respectively. Furthermore, both DHA and ARA uniquely altered the structure and toxicity of the corresponding protein aggregates. Our objective is to ascertain whether other LCPUFAs, alongside long-chain unsaturated fatty acid (LCUFA) proteins, exhibit similar effects on amyloidogenic proteins. To explore this matter, we investigated the effect of 10 different LCPUFAs and LCUFAs on the rate of insulin aggregation. We found that all of the analyzed fatty acids strongly accelerated insulin aggregation. Moreover, we found that protein aggregates that were formed in the presence of these fatty acids exerted significantly higher cell toxicity compared with insulin fibrils grown in the lipid-free environment. These findings show that interactions between amyloid-associated proteins and LCPUFAs can be the underlying molecular cause of neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Morphological Examination Of Insulin Aggregates Grown In The...mentioning

confidence: 90%

Long-Chain Polyunsaturated Fatty Acids Accelerate the Rate of Insulin Aggregation and Enhance Toxicity of Insulin Aggregates

Hoover,

Lynn,

Zhaliazka

et al. 2023

ACS Chem. Neurosci.

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“…It was also found that hydrophobic interactions between insulin and FAs were strongly altered by the number of carbon atoms in FAs and the degree of their unsaturation. 50 The results summarized in this Account also suggest that the onset and progression of amyloid diseases could be linked to the pathological changes in plasma membranes. For instance, an increase in the concentration of PS in the external membrane, which takes place in the case of cell malfunctioning, can trigger the aggregation of amyloidogenic proteins.…”

Section: ■ Concluding Remarksmentioning

confidence: 90%

“…As a result, inulin:FAs complexes formed fibrils with opposite supramolecular chirality compared to those developed by insulin in a lipid-free environment. It was also found that hydrophobic interactions between insulin and FAs were strongly altered by the number of carbon atoms in FAs and the degree of their unsaturation …”

Section: Discussionmentioning

confidence: 99%

“…These findings show that protein:lipid and protein:FA interactions should be strongly considered upon the search for effective drug candidates that would inhibit protein aggregation. Using docking simulations, Holman and co-workers recently demonstrated that such hydrophobic forces primarily determined the interactions between insulin and FAs . As a result, inulin:FAs complexes formed fibrils with opposite supramolecular chirality compared to those developed by insulin in a lipid-free environment.…”

Section: Discussionmentioning

confidence: 99%

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Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins

Kurouski

2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS:The abrupt aggregation of misfolded proteins is linked to the onset and spread of amyloidogenic diseases, including diabetes type 2, systemic amyloidosis, and Alzheimer's (AD) and Parkinson's diseases (PD). Although the exact cause of these pathological processes is unknown, a growing body of evidence suggests that amyloid diseases are triggered by misfolded or unfolded proteins, forming highly toxic oligomers. These transient species exhibit high structural and morphological heterogeneity. Protein oligomers can also propagate into β-sheet-rich filaments that braid and coil with other filaments to form amyloid fibrils and supramolecular structures with both flat and twisted morphologies. Microscopic examination of protein deposits formed in the brains of both AD and PD patients revealed the presence of fragments of lipid membranes. Furthermore, nanoscale infrared analysis of ex vivo extracted fibrils revealed the presence of lipids in their structure (Zhaliazka, K.; Kurouski, D.Protein Sci. 2023, 32, e4598). These findings demonstrated that lipid bilayers could play an important role in the aggregation of misfolded proteins. Experimental findings summarized in this Account show that (i) lipids uniquely change the aggregation rate of amyloidogenic proteins. In this case, the observed changes in the rates directly depend on the net charge of the lipid and the length and saturation of lipid fatty acids (FAs). For instance, zwitterionic phosphatidylcholine (PC) with 14:0 FAs inhibited the aggregation of insulin, lysozyme, and α-synuclein (α-Syn), whereas anionic phosphatidylserine with the same FAs dramatically accelerated the aggregation rate of these proteins (Dou, T., et al.

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Tubulin‐binding region alters tau–lipid interactions and changes toxicity of tau fibrils formed in the presence of phosphatidylserine lipids

Ali,

Holman,

Rodriguez

et al. 2024

Protein Science

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Alzheimer's disease is the fastest‐growing neurodegenerative disease that affects over six million Americans. The abnormal aggregation of amyloid β peptide and Tau protein is the expected molecular cause of the loss of neurons in brains of AD patients. A growing body of evidence indicates that lipids can alter the aggregation rate of amyloid β peptide and modify the toxicity of amyloid β aggregates. However, the role of lipids in Tau aggregation remains unclear. In this study, we utilized a set of biophysical methods to determine the extent to which phospatidylserine (PS) altered the aggregation properties of Tau isoforms with one (1N4R) and two (2N4R) N terminal inserts that enhance the binding of Tau to tubulin. We found that the length and saturation of fatty acids (FAs) in PS altered the aggregation rate of 2N4R isoform, while no changes in the aggregation rate of 1N4R were observed. These results indicate that N terminal inserts play an important role in protein–lipid interactions. We also found that PS could change the toxicity of 1N4R and 2N4R Tau fibrils, as well as alter molecular mechanisms by which these aggregates exert cytotoxicity to neurons. Finally, we found that although Tau fibrils formed in the presence and absence of PS endocytosed by cells, only fibril species that were formed in the presence of PS exert strong impairment of the cell mitochondria.

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Fatty Acids Reverse the Supramolecular Chirality of Insulin Fibrils

Cited by 9 publications

References 30 publications

Long-Chain Polyunsaturated Fatty Acids Accelerate the Rate of Insulin Aggregation and Enhance Toxicity of Insulin Aggregates

Long-Chain Polyunsaturated Fatty Acids Accelerate the Rate of Insulin Aggregation and Enhance Toxicity of Insulin Aggregates

Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins

Tubulin‐binding region alters tau–lipid interactions and changes toxicity of tau fibrils formed in the presence of phosphatidylserine lipids

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