Conservation of the Amyloid Interactome Across Diverse Fibrillar Structures

Sci Rep. 2019 Mar 7;9(1):3863. doi: 10.1038/s41598-019-40483-z.

Abstract

Several human proteins cause disease by misfolding and aggregating into amyloid fibril deposits affecting the surrounding tissues. Multiple other proteins co-associate with the diseased deposits but little is known about how this association is influenced by the nature of the amyloid aggregate and the properties of the amyloid-forming protein. In this study, we investigated the co-aggregation of plasma and cerebrospinal proteins in the presence of pre-formed amyloid fibrils. We evaluated the fibril-associated proteome across multiple amyloid fibril types that differ in their amino acid sequences, ultrastructural morphologies, and recognition by amyloid-binding dyes. The fibril types included aggregates formed by Amyloid β, α-synuclein, and FAS4 that are associated with pathological disorders, and aggregates formed by the glucagon and C-36 peptides, currently not linked to any human disease. Our results highlighted a highly similar response to the amyloid fold within the body fluid of interest. Fibrils with diverse primary sequences and ultrastructural morphologies only differed slightly in the composition of the co-aggregated proteins but were clearly distinct from less fibrillar and amorphous aggregates. The type of body fluid greatly affected the resulting amyloid interactome, underlining the role of the in vivo environment. We conclude that protein fibrils lead to a specific response in protein co-aggregation and discuss the effects hereof in the context of amyloid deposition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / genetics
  • Amyloid / metabolism*
  • Amyloid / ultrastructure
  • Cerebrospinal Fluid / metabolism
  • Humans
  • Ligands
  • Plasma / metabolism
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Binding
  • Protein Conformation

Substances

  • Amyloid
  • Ligands