Abstract
Alpha-synuclein (α-Syn) is a small presynaptic protein of 140 amino acids. Its pathologic intracellular aggregation within the central nervous system yields protein fibrillar inclusions named Lewy bodies that are the hallmarks of Parkinson’s disease (PD). In solution, pure α-Syn adopts an intrinsically disordered structure and assembles into fibrils that exhibit considerable morphological heterogeneity depending on their assembly conditions. We recently established tightly controlled experimental conditions allowing the assembly of α-Syn into highly homogeneous and pure polymorphs. The latter exhibited differences in their shape, their structure but also in their functional properties. We have conducted an AFM study at high resolution and performed a statistical analysis of fibrillar α-Syn shape and thermal fluctuations to calculate the persistence length to further assess the nanomechanical properties of α-Syn polymorphs. Herein, we demonstrated quantitatively that distinct polymorphs made of the same protein (wild-type α-Syn) show significant differences in their morphology (height, width and periodicity) and physical properties (persistence length, bending rigidity and axial Young’s modulus).
Highlights
To further document the physical properties of the two polymorphs we characterized structurally and functionally and that of two additional polymorphs we generated, we have imaged the four fibrillar α-Syn polymorphs by atomic force microscopy (AFM) in air and performed a statistical analysis of the shape and thermal shape fluctuations[25,26,27,28] on two different substrates to take into account the possible effect of the underlying substrate to fibrils properties[29]
As the assembly conditions of α-Syn have been repeatedly shown to influence the nature of the fibrillar particles that form and their homogeneity[1,22,23,30,32], we revisited α-Syn assembly into fibrils under tightly controlled experimental conditions
Transmission electron microscopy analysis reveals that while the polymorph generated at pH 7.5 and in the presence of 150 mM KCl has a cylindrical aspect (Fig. 1a), that obtained at the same pH but under low salt conditions (
Summary
To further document the physical properties of the two polymorphs we characterized structurally and functionally and that of two additional polymorphs we generated, we have imaged the four fibrillar α-Syn polymorphs by atomic force microscopy (AFM) in air and performed a statistical analysis of the shape and thermal shape fluctuations[25,26,27,28] on two different substrates to take into account the possible effect of the underlying substrate to fibrils properties[29]. We demonstrate here that distinct fibrillar strains made of the same protein differ very significantly by their physical properties
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