Abstract
The misfolding and self-assembly of intrinsically disordered proteins into insoluble amyloid structures are central to many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Optical imaging of this self-assembly process in vitro and in cells is revolutionizing our understanding of the molecular mechanisms behind these devastating conditions. In contrast to conventional biophysical methods, optical imaging and, in particular, optical superresolution imaging, permits the dynamic investigation of the molecular self-assembly process in vitro and in cells, at molecular-level resolution. In this article, current state-of-the-art imaging methods are reviewed and discussed in the context of research into neurodegeneration.
Highlights
Proteins have an intrinsic propensity to self-assemble into aggregates
Aggregation propagates the misfolded protein state and this phenomenon is at the heart of a number of so-called “protein misfolding diseases.”[2,3] A key problem in misfolding diseases is that normal protein homeostasis is disrupted in the cell, as aggregation lowers the propensity of the protein pool to remain soluble
Small oligomeric species may elicit toxicity directly through interference with vital metabolic processes in the cell. These problems are at the heart of major neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), in which usually harmless, soluble proteins self-assemble into highly regular, fibrillar aggregate structures called amyloids,[4] which may elicit structure-specific phenotypes
Summary
Proteins have an intrinsic propensity to self-assemble into aggregates. The process is initiated by the formation of an aggregation-nucleus from the native monomers; this is a small oligomeric species consisting of only a few monomer units, from which aggregation proceeds via association of further monomers. The nucleus is a unit for which the rate of further monomer association is larger than that of dissociation Such oligomers are called “on-pathway” species, because their presence increases the propensity of the protein pool to aggregate. Small oligomeric species may elicit toxicity directly through interference with vital metabolic processes in the cell These problems are at the heart of major neurodegenerative diseases, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), in which usually harmless, soluble proteins self-assemble into highly regular, fibrillar aggregate structures called amyloids,[4] which may elicit structure-specific phenotypes. We review the application of single-molecule superresolution microscopy, which reveals morphological information of single aggregate clusters at the molecular scale
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