Abstract
Misfolding and aggregation of the proteins amyloid-β, tau and alpha-synuclein is the predominant pathology underlying the neurodegenerative disorders, Alzheimer's and Parkinson's disease. While end stage insoluble products of aggregation have been well characterised in human and animal models of disease, accumulating evidence from biophysical, cellular and invivo studies has shown that soluble intermediates of aggregation, or oligomers, may be the key species that mediate toxicity and underlie seeding and spreading in disease. Here, we review the process of protein misfolding, and the intrinsic and extrinsic processes that cause the native states of the key aggregating proteins to undergo conformational change to form oligomers and ultimately fibrils. We discuss the structural features of the key toxic intermediate, and describe the putative mechanisms by which oligomers may cause cell toxicity. Finally, we explore the potential therapeutic approaches raised by the oligomer hypothesis in neurodegenerative disease.
Highlights
Protein misfolding and aggregation are molecular processes known to occur in all neurodegenerative disorders, including the commonest diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD)
We provide a range of evidence to support the hypothesis that oligomeric species are crucial in mediating cell toxicity in neurodegenerative diseases
The recognition of the importance of the oligomer has spurred progress in methods to enable the detection of rare protein species to address this challenge
Summary
Protein misfolding and aggregation are molecular processes known to occur in all neurodegenerative disorders, including the commonest diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD). Intrinsically disordered monomeric proteins (such as Ab and tau in AD, and a-syn in PD), undergo conformational changes from their native states into highly ordered b-sheet rich fibrillar amyloid structures [1]. The detection of these amyloid structures in postmortem brain tissue has allowed accurate post-mortem diagnosis of subtypes of neurodegenerative diseases. Native states and the role of oligomeric species in neurodegenerative diseases Natively, the proteins of the major components in neurodegenerative diseases such as a-syn, Ab and tau are classified as intrinsically disordered proteins (IDP) that lack a fixed or stable three-dimensional structure Instead, they retain conformational freedom in association with other molecules, and can adopt a range of different structures, a property that is key to their wide biological functions (Box 1). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
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