Year: 2022
Type: article
Abstract: Amyloid peptides nucleate from monomers to aggregate into fibrils through primary nucleation; pre-existing fibrils can then act as seeds for additional monomers to fibrillize through secondary nucleation. Both nucleation processes can occur simultaneously, yielding a distribution of fibril polymorphs that can generate a spectrum of neurodegenerative effects. Understanding the mechanisms driving polymorph structural distribution during both nucleation processes is important for uncovering fibril structure-function relationships, as well creating polymorph distributions in vitro that better match distributions found in vivo . Here, we explore how cross-seeding WT Aβ 1-40 with Aβ 1-40 mutants E22G (Arctic) and E22Δ (Osaka), as well as with WT Aβ 1-42 affects the distribution of fibril structural polymorphs, and how changes in structural distribution impact toxicity. Transmission electron microscopy analysis reveals that fibril seeds derived from mutants of Aβ 1-40 impart their structure to WT Aβ 1-40 monomer during secondary nucleation, but WT Aβ 1-40 fibril seeds do not affect the structure of fibrils assembled from mutant Aβ 1-40 monomers, despite kinetics data indicating accelerated aggregation when cross-seeding of any combination of mutants. Additionally, WT Aβ 1-40 fibrils seeded with mutant fibrils to produce similar structural distributions to the mutant seeds also produced similar cytotoxicity on neuroblastoma cell lines. This indicates that mutant fibril seeds not only impart their structure to growing WT Aβ 1-40 aggregates, but they also impart cytotoxic properties. Our findings provide clear evidence that there is a relationship between fibril structure and phenotype on a polymorph population level, and that these properties can be passed on through secondary nucleation of succeeding generations of fibrils.
Authors: Michael J. Lucas, Henry S. Pan, Eric J. Verbeke, Gina Partipilo, Ethan C. Helfman, Leah Kann, Benjamin K. Keitz, David W. Taylor, Lauren J. Webb
Institution: The University of Texas at Austin
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, Welch Foundation, Cancer Prevention and Research Institute of Texas, University of Texas at Austin, National Institutes of Health, College of Natural Sciences, University of Texas at Austin, Division of Materials Research, Division of Graduate Education, Division of Chemistry, Army Research Office
Awards: G1056835623, G1377326687, G1449763142, G1500824199, G2049235933, G2068707083, G2279853913, G3024053924, G3051044190, G4682064022, Center for Dynamics and Control of Materials, G5295616565, G608057831, G6725192607, Recruitment of First-Time, Tenure-Track Faculty Members, G7334195024, G7433113547, G7452299184, G7698605067, Formation, Hydration, and Structure of Biomolecules at the Protein-Surface Interface, G8415477955, G8872807966
OpenAlex ID: W4220680331