Learn More
The phenomenon of protein aggregation and amyloid formation has become the subject of rapidly increasing research activities across a wide range of scientific disciplines. Such activities have been stimulated by the association of amyloid deposition with a range of debilitating medical disorders, from Alzheimer's disease to type II diabetes, many of which(More)
Studies of proteins' formation of amyloid fibrils have revealed that potentially cytotoxic oligomers frequently accumulate during fibril formation. An important question in the context of mechanistic studies of this process is whether or not oligomers are intermediates in the process of amyloid fibril formation, either as precursors of fibrils or as species(More)
Protein molecules have the ability to form a rich variety of natural and artificial structures and materials. We show that amyloid fibrils, ordered supramolecular nanostructures that are self-assembled from a wide range of polypeptide molecules, have rigidities varying over four orders of magnitude, and constitute a class of high-performance biomaterials.(More)
We report the detailed mechanical characterization of individual amyloid fibrils by atomic force microscopy and spectroscopy. These self-assembling materials, formed here from the protein insulin, were shown to have a strength of 0.6 +/- 0.4 GPa, comparable to that of steel (0.6-1.8 GPa), and a mechanical stiffness, as measured by Young's modulus, of 3.3(More)
The generation of toxic oligomers during the aggregation of the amyloid-β (Aβ) peptide Aβ42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer's disease, but the molecular pathways that control pathological aggregation have proved challenging to identify. Here, we use a combination of kinetic studies,(More)
Soluble oligomeric aggregates of the amyloid-beta peptide (Abeta) have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the conformation adopted by Abeta within these aggregates is not known, a beta-hairpin conformation is known to be accessible to monomeric Abeta. Here we show that this beta-hairpin is a building block of toxic(More)
We present an analytical treatment of a set of coupled kinetic equations that governs the self-assembly of filamentous molecular structures. Application to the case of protein aggregation demonstrates that the kinetics of amyloid growth can often be dominated by secondary rather than by primary nucleation events. Our results further reveal a range of(More)
We describe the isolation and detailed structural characterization of stable toxic oligomers of α-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction(More)
α-Synuclein (α-syn) is the major component of filamentous Lewy bodies found in the brains of patients diagnosed with Parkinson's disease (PD). Recent studies demonstrate that, in addition to the wild-type sequence, α-syn is found in several modified forms, including truncated and phosphorylated species. Although the mechanism by which the neuronal loss in(More)
α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other(More)