![]() ![]() Recent advances in structural studies of amyloid fibrils using solid-state nuclear magnetic resonance, electron diffraction, X-ray diffraction and cryo-electron microscopy (cryo-EM) have extended our understanding of the complexities of amyloid fibril structures in relation to pathology. For example, assembly of the α-synuclein protein into amyloid aggregates is associated with Parkinson’s disease (PD), Lewy body dementia (LBD), multiple system atrophy (MSA), and other synucleinopathies. The formation of amyloid structures is observed in association with many human neurodegenerative diseases. The non-covalent intermolecular forces within the cross-β amyloid cores running parallel to the fibril axis, from the β-strands that are oriented perpendicularly to the fibril axis, stabilises the amyloid structure, making them strong and biochemically resilient assemblies. These conclusions show that fragmentation stabilities of different amyloid fibril polymorph structures can be diverse and suggest that the approach we report here will be useful in comparing the relative stabilities of amyloid fibril types or fibril polymorphs toward fragmentation under different biological conditions.Īmyloid fibrils are proteinaceous polymers characterized by their cross-β core molecular structure. Our results demonstrate that the fibril fragmentation stabilities of these different α-synuclein fibril polymorphs are all highly length dependent but distinct, with both A30P and A53T α-synuclein fibrils displaying increased resistance towards sonication-induced fibril fragmentation compared with WT α-synuclein fibrils. This approach is applied to assess the relative fragmentation stabilities of amyloid formed in vitro from wild type (WT) α-synuclein and two familial mutant variants of α-synuclein (A30P and A53T) that generate morphologically different fibril structures. In this study, we show that controlled sonication, a widely used method of mechanical perturbation for amyloid seed generation, can be used as a form of mechanical perturbation for rapid comparative assessment of the relative fragmentation stabilities of different amyloid fibril structures. We have previously developed an approach to compare the relative stabilities of different types of amyloid fibrils toward fragmentation. However, despite the mechanistic importance of fibril fragmentation, the relative stabilities of different types or different polymorphs of amyloid fibrils toward fragmentation remain to be quantified. Fragmentation of amyloid fibrils plays a crucial role in the propagation of the amyloid state encoded in their three-dimensional structures and may have an important role in the spreading of potentially pathological properties and phenotypes in amyloid-associated diseases. The division of amyloid fibril particles through fragmentation is implicated in the progression of human neurodegenerative disorders such as Parkinson’s disease. ![]()
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