Key Points
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The phenomenon of amyloid formation is associated with protein misfolding disorders, including Alzheimer's disease, Parkinson's disease and type II diabetes.
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The amyloid state is a 'generic state' of proteins and its study can provide great insight into the nature of functional structures and into that of disease-related assemblies.
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A multitude of quality control, or 'housekeeping', mechanisms exist in living organisms to prevent the conversion of normally soluble proteins into the aberrant amyloid state and to maintain protein homeostasis.
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The failure of these quality control mechanisms can give rise to 'protein metastasis', the uncontrolled conversion of these molecules into aberrant self-propagating assemblies that ultimately lead to a cascade of cytotoxic processes.
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Our increasing ability to monitor and characterize the molecular structures and formation mechanisms of the protein species that are involved in amyloid formation is suggesting novel strategies to treat or prevent protein misfolding disorders.
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Ultimately, the results of this field of research will result in great changes in the way we are able to manage modern lifestyles and maintain healthy ageing.
Abstract
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 are major threats to human health and welfare in the modern world. It has become clear, however, that the ability to form the amyloid state is more general than previously imagined, and that its study can provide unique insights into the nature of the functional forms of peptides and proteins, as well as understanding the means by which protein homeostasis can be maintained and protein metastasis avoided.
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Change history
12 June 2014
In the legend of figure 2 of the above article (page 388), the sentence “The spacing between polypeptide chains along the fibril axis is constant to a good approximation even for very different polypeptide sequences, a generic property arising from the common inter-side chain hydrogen bonding constraints (orange line in part b).” incorrectly referred to 'inter-side chain' hydrogen bonding constraints, whereas it should have referred to 'inter-main chain' hydrogen bonding constraints. This has been corrected online. The authors apologize for any confusion caused to readers.
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Acknowledgements
The authors acknowledge with tremendous gratitude the many graduate students, postdoctoral fellows, collaborators and other colleagues whose discoveries and ideas are reflected in this Review — many of their names are included in the citations to published work. They are also very grateful to the many organizations that have funded their research over many years, including the Wellcome Trust, the Leverhulme Trust, the Alzheimer's Research Trust, Parkinson's UK, the Frances and Augustus Newman Foundation, the European Commission, UK Research Councils and Elan Pharmaceuticals.
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Glossary
- Intrinsic
-
In the case of a protein, a property that only depends on its amino acid sequence.
- Protein solubility
-
The concentration of the soluble fraction of a protein in equilibrium with the insoluble fraction. This thermodynamic definition, in the presence of high kinetic barriers between the various soluble and insoluble states of a protein, may, however, need to be extended to include kinetic factors.
- Protein homeostasis
-
The ensemble of cellular processes that regulates the behaviour of proteins in terms of their conformations, interactions, concentrations and localizations.
- Generic
-
In the case of proteins, a property that is common to most of them, as opposed to 'specific' properties. Such generic properties are often associated with the backbone that is common to all polypeptide molecules, whereas specific properties arise from the variations in the chemistry that is mediated by the side chains.
- Chirality
-
The characteristic of a molecular structure that does not have mirror symmetry.
- Young's modulus
-
A measure of the elastic properties of a material, defined as the ratio between stress and strain along a given axis.
- Nucleation
-
In the transition from a fluid phase to a condensed phase, a process that generates species within the fluid phase that are capable of growing into the condensed phase.
- Templating
-
A phenomenon in which structured aggregates promote the conversion of soluble protein species into similar aggregates.
- Seeding
-
A phenomenon in nucleated growth processes by which nuclei of the aggregated phase promote the formation of larger aggregates.
- Primary nucleation
-
A nucleation process that takes place by the spontaneous assembly of monomeric species.
- Secondary nucleation
-
A process by which the formation of new nuclei in the aggregated phase is catalysed by existing aggregates.
- Spreading
-
In the context of neurodegeneration, the spatial propagation of amyloid assemblies from cell to cell by a series of diffusion or transport mechanisms that are coupled with seeding or templating processes.
- Cooperativity
-
A property of a system that results from its collective behaviour, but it is not exhibited by its component parts.
- Molecular chaperones
-
Proteins that assist the protein-folding process, the maintenance of the soluble state of proteins and more generally contribute to generating and preserving protein homeostasis.
- Systemic amyloidoses
-
A group of diseases characterized by the widespread deposition of amyloid aggregates in organs and tissues.
- Protein metastasis
-
The ensemble of molecular processes whereby the functional soluble states of proteins convert into self-propagating aberrant assemblies that initiate a cascade of cytotoxic events.
- Supersaturated
-
A condition in which a soluble substance is concentrated to a level above its critical value but kinetic barriers delay its transition to an insoluble state.
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Knowles, T., Vendruscolo, M. & Dobson, C. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15, 384–396 (2014). https://doi.org/10.1038/nrm3810
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DOI: https://doi.org/10.1038/nrm3810
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