Elucidating the Role of Lipids in the Aggregation of Amyloidogenic Proteins

Abstract

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.

Transcellular transmission and molecular heterogeneity of aggregation-prone proteins in neurodegenerative diseases

“…Indeed, different neurodegenerative diseases differ in the composition of biomolecules in specific neuronal cell populations ( Peng et al, 2018 , Shaw and Eggett, 2000 ). The molecules targeting specific biomolecules include lipids and ions such as Ca 2+ , and it is thought that the interaction of these biomolecules with proteins can alter the degree of protein aggregation ( Beasley et al, 2022 , Beasley et al, 2021 , Binolfi et al, 2008 , Chen et al, 2023 , Dou and Kurouski, 2022 , Kurouski, 2023 , Lautenschlager et al, 2018 , Stonebraker et al, 2023 , Zunke et al, 2018 ).…”