Lipid Dynamics and Phase Transition within α-Synuclein Amyloid Fibrils

Abstract

The deposition of coassemblies made of the small presynaptic protein, α-synuclein, and lipids in the brains of patients is the hallmark of Parkinson’s disease. In this study, we used natural abundance 13C and 31P magic-angle spinning nuclear magnetic resonance spectroscopy together with cryo-electron microscopy and differential scanning calorimetry to characterize the fibrils formed by α-synuclein in the presence of vesicles made of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine or 1,2-dilauroyl-sn-glycero-3-phospho-L-serine. Our results show that these lipids coassemble with α-synuclein molecules to give thin and curly amyloid fibrils. The coassembly leads to slower and more isotropic reorientation of lipid molecular segments and a decrease in both the temperature and enthalpy of the lipid chain-melting compared with those in the protein-free lipid lamellar phase. These findings provide new insights into the properties of lipids within protein–lipid assemblies that can be associated with Parkinson’s disease.

A series of helical α-synuclein fibril polymorphs are populated in the presence of lipid vesicles

“…2a). During this time distinctive fibril-like structures were observed to emerge from the surface of the SUVs that are similar to those reported by others in the presence of DMPS 6,15 . In particular, these meandering fibril-like structures, were~5 nm in diameter, suggesting that they are protofibrils of the singlestranded variety 2 .…”

“…α-Synuclein (αS), which has been described as intrinsically disordered or helical, is capable, under certain conditions, of aggregating into a range of different amyloid fibril morphologies 1 . These structures are typically probed via imaging techniques that include electron microscopy (EM) and atomic force microscopy, and more recently at the atomic level using solid-state nuclear magnetic resonance 2 , and increasingly, cryoEM [3][4][5][6][7][8] . Many approaches describe structures gained via recombinant means under in vitro conditions [2][3][4][5]7,9,10 .…”

“…Many approaches describe structures gained via recombinant means under in vitro conditions [2][3][4][5]7,9,10 . Others have employed the use of lipids during in vitro experiments, since this is critical to αS function in situ 6,[11][12][13][14][15][16][17] . More recent studies are emerging in which aggregates of αS from specific neurodegenerative diseases and key regions of the brain are isolated in small quantities 8,18 .…”

Self-Assembly in Ganglioside‒Phospholipid Systems: The Co-Existence of Vesicles, Micelles, and Discs

“…These experiments provide information on the mobility and conformation in different segments of the lipid molecules with close-to-atomic resolution [37,38]. The same experimental approach has previously been used to yield atomically resolved information on molecular dynamics in lipids and surfactants [38,39] and in amyloid fibrils [40,41], as well as in samples with a complex composition from lung surfactant [42], cartilage [43], and skin stratum corneum [44]. Three different NMR experiments were performed for each sample: DP (direct polarization), CP (cross-polarization), and INEPT (insensitive nuclei enhanced by polarization transfer).…”

Rapid formation of peptide/lipid co-aggregates by the amyloidogenic seminal peptide PAP248-286

“…Lipid membranes are known to promote aggregation of various amyloid-forming peptides (30, 31), and can alter the morphology of the resulting aggregates (32–34). In many cases, the lipid remains closely associated with the aggregated peptide (35, 36). Stable tau/lipid oligomers and α-synuclein lipopeptide nanoparticles have been suggested to be important in the pathogenesis of tauopathies and synucleinopathies, respectively (37–39).…”