Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons

Michael A. Metrick, Natalia do Carmo Ferreira, Eri Saijo, Andrew G. Hughson, Allison Kraus, Christina Orrú, Michael W. Miller, Gianluigi Zanusso, Bernardino Ghetti, Michele Vendruscolo, Byron Caughey

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Recent work with prion diseases and synucleinopathies indicates that accurate diagnostic methods for protein-folding diseases can be based on the ultrasensitive, amplified measurement of pathological aggregates in biospecimens. A better understanding of the physicochemical factors that control the seeded polymerization of such aggregates, and their amplification in vitro, should allow improvements in existing assay platforms, as well as the development of new assays for other proteopathic aggregates. Here, we systematically investigated the effects of the ionic environment on the polymerization of tau, α-synuclein, and the prion protein (PrP) induced by aggregates in biospecimens. We screened salts of the Hofmeister series, a relative ordering of strongly and weakly hydrated salts that tend to precipitate or solubilize proteins. We found that sensitivities of tau-based assays for Alzheimer’s seeds and PrP-based assays for prions were best in weakly hydrated anions. In contrast, we saw an inverse trend with different tau-based assays, improving detection sensitivity for progressive supranuclear palsy seeds by ≈106. Hofmeister analysis also improved detection of sporadic Creutzfeldt–Jakob disease prions in human nasal brushings and chronic wasting disease prions in deer-ear homogenates. Our results demonstrate strong and divergent influences of ionic environments on the amplification and detection of proteopathic seeds as biomarkers for protein-folding diseases.

Original languageEnglish (US)
Pages (from-to)23029-23039
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number46
DOIs
StatePublished - Nov 12 2019

Keywords

  • Hofmeister series
  • Ion hydration
  • Protein misfolding
  • RT-QuIC
  • Tau

ASJC Scopus subject areas

  • General

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    Metrick, M. A., do Carmo Ferreira, N., Saijo, E., Hughson, A. G., Kraus, A., Orrú, C., Miller, M. W., Zanusso, G., Ghetti, B., Vendruscolo, M., & Caughey, B. (2019). Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons. Proceedings of the National Academy of Sciences of the United States of America, 116(46), 23029-23039. https://doi.org/10.1073/pnas.1909322116