Abstract
ABSTRACTAmyloid fibrils are protein homopolymers that adopt diverse cross-β conformations. Some amyloid fibrils are associated with the pathogenesis of devastating neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Conversely, functional amyloids play beneficial roles in melanosome biogenesis, long-term memory formation and release of peptide hormones. Here, we showcase advances in our understanding of amyloid assembly and structure, and how distinct amyloid strains formed by the same protein can cause distinct neurodegenerative diseases. We discuss how mutant steric zippers promote deleterious amyloidogenesis and aberrant liquid-to-gel phase transitions. We also highlight effective strategies to combat amyloidogenesis and related toxicity, including: (1) small-molecule drugs (e.g. tafamidis) to inhibit amyloid formation or (2) stimulate amyloid degradation by the proteasome and autophagy, and (3) protein disaggregases that disassemble toxic amyloid and soluble oligomers. We anticipate that these advances will inspire therapeutics for several fatal neurodegenerative diseases.
Highlights
Amyloid fibrils are protein homopolymers that adopt diverse cross-β conformations (Fig. 1A). These non-branching fibrils are stabilized via intermolecular contacts between β-strands, which align orthogonally to the fibril axis to yield cross-β architecture (Fig. 1A) (Eanes and Glenner, 1968; Sipe and Cohen, 2000; Sunde et al, 1997)
Insulin amyloids have a strength of ∼0.6±0.4 GPa, which is comparable to that shown by steel (∼0.6–1.8 GPa) (Knowles and Buehler, 2011; Smith et al, 2006)
There are likely universal gain-of-toxicity mechanisms induced by amyloid fibrils or soluble misfolded oligomers, which may be exacerbated by the loss of native protein function
Summary
Amyloid fibrils are protein homopolymers that adopt diverse cross-β conformations (Fig. 1A). There are likely universal gain-of-toxicity mechanisms induced by amyloid fibrils or soluble misfolded oligomers, which may be exacerbated by the loss of native protein function While this generic toxicity unleashes havoc in the context of disease, nature has quenched this toxicity and deployed amyloid for functional purposes (Bergman et al, 2016; Harvey et al, 2017; Hufnagel et al, 2013; Jarosz and Khurana, 2017; Watt et al, 2013). This region is similar to the prion domain in Aplysia CPEB, which enables Aplysia CPEB to form infectious amyloids, termed prions
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