Protease resistance of ex vivo amyloid fibrils implies the proteolytic selection of disease-associated fibril morphologies

Jonathan Schönfelder, Peter Benedikt Pfeiffer, Tejaswini Pradhan, Johan Bijzet, Bouke P.C. Hazenberg, Stefan O. Schönland, Ute Hegenbart, Bernd Reif, Christian Haupt, Marcus Fändrich

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26 Scopus citations

Abstract

Several studies recently showed that ex vivo fibrils from patient or animal tissue were structurally different from in vitro formed fibrils from the same polypeptide chain. Analysis of serum amyloid A (SAA) and Aβ-derived amyloid fibrils additionally revealed that ex vivo fibrils were more protease stable than in vitro fibrils. These observations gave rise to the proteolytic selection hypothesis that suggested that disease-associated amyloid fibrils were selected inside the body by their ability to resist endogenous clearance mechanisms. We here show, for more than twenty different fibril samples, that ex vivo fibrils are more protease stable than in vitro fibrils. These data support the idea of a proteolytic selection of pathogenic amyloid fibril morphologies and help to explain why only few amino acid sequences lead to amyloid diseases, although many, if not all, polypeptide chains can form amyloid fibrils in vitro.

Original languageEnglish
Pages (from-to)243-251
Number of pages9
JournalAmyloid
Volume28
Issue number4
DOIs
StatePublished - 2021

Keywords

  • Amyloid structure
  • prion
  • protein misfolding
  • proteolytic stability; immunoglobulin light chain
  • transthyretin; serum amyloid A

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