Key Points
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The misfolding and/or misassembly of more than 30 human proteins — for example, transthyretin, immunoglobulin light chain, serum amyloid A and amyloid-β — into various aggregate structures, a process known as amyloidogenesis, cause a range of degenerative disorders, collectively called amyloid diseases.
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Amyloidogenesis is a dynamic process; thus, the protein aggregates produced adopt a range of structures ranging from small, relatively unstructured oligomers to structurally well-defined cross-β-sheet amyloid fibrils. Some structures may only be produced in humans.
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Although there is mounting genetic and pharmacological evidence that the process of protein aggregation is an important driver of neurodegeneration, a structure–proteotoxicity relationship is lacking for all human amyloid diseases. Moreover, we do not understand how the process of aggregation leads to the loss of postmitotic tissue in any human amyloid disease.
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In this Review, we summarize current and emerging strategies to ameliorate degenerative disorders associated with protein aggregation, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates.
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Potential therapeutic strategies for degenerative disorders associated with protein aggregation include: protein stabilization to prevent the conformational changes that enable aggregation, protein reduction to lower the concentration of the aggregation-prone protein and thereby slow aggregation, aggregate clearance or remodelling to reduce proteotoxicity, cellular proteostasis network adaptation to enhance proteome quality control, and reducing seeding and cell-to-cell spreading.
Abstract
The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure–activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.
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Acknowledgements
The authors thank the reviewers for their critical and insightful comments that shaped their thinking and helped to improve the manuscript. Y.S.E. expresses particular thanks to M. Jucker, Tübingen, Germany, for helpful discussions and for his mentorship. The authors are supported by US National Institutes of Health grants DK46335 (to J.W.K.), AG46495 (to J.W.K.) and GM101644 (to E.T.P.). Y.S.E. is supported by a postdoctoral fellowship from the German Academic Exchange Service (DAAD). The authors apologize to colleagues whose work they were unable to include owing to space limitations.
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J.W.K. and E.T.P. discovered tafamidis, and J.W.K. founded FoldRx to commercialize it. FoldRx is now owned by Pfizer, in which both J.W.K. and E.T.P. have a financial interest. J.W.K. is a shareholder and a paid consultant for Pfizer, which sells tafamidis. J.W.K. and E.T.P. receive royalty payments from the sale of tafamidis. Y.S.E., C.M., C.F., S.E.E. and R.L.W. declare no competing financial interests.
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DATABASES
Glossary
- Amyloid fibrils
-
Lateral assemblies of protein aggregates adopting a cross-β-sheet structure. These aggregates bind to Congo red, thioflavin T and analogous aromatics.
- Amyloidogenesis
-
The process of protein aggregation in an organism whereby physical chemical forces and biological modifiers together influence the aggregate structural ensembles afforded.
- Proteostasis network
-
The macromolecular machinery that generates, folds, moves and degrades the proteome. Proteostasis network components include chaperones, the proteasome, trafficking machinery and various enzymes — such as disulfide isomerases — that act on the proteome.
- Nucleus
-
An energetically unfavourable, sparsely populated, typically oligomeric species that is thought to be rich in β-sheet structure. Nucleus formation is the rate-limiting step for efficient aggregation in a nucleation-dependent polymerization; it is followed by rapid monomer addition, which produces a seed.
- Seeds
-
Stable aggregates that result from the addition of monomers to a nucleus or that arise from the fragmentation of fibrils. Seeds enable homotypic protein aggregation without a requirement for nucleus formation, as seeded aggregation bypasses the requirement for a nucleation step.
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Eisele, Y., Monteiro, C., Fearns, C. et al. Targeting protein aggregation for the treatment of degenerative diseases. Nat Rev Drug Discov 14, 759–780 (2015). https://doi.org/10.1038/nrd4593
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DOI: https://doi.org/10.1038/nrd4593
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