Cross-amyloid aggregation of different amyloid proteins (i.e. cross-seeding) is speculated as a main mechanism for the spread of amyloidogenesis across different cells and tissues between different amyloid-misfolding diseases (PMDs). However, the cross-seeding is still a subject poorly explored and little is known about its sequence/structure-dependent aggregation mechanisms, as compared to the widely studied homo-seeding aggregation. Herein, we are the first to report that GNNQQNY – a short fragment from yeast prion protein Sup35 – can serve as a general cross-β structural template to cross-interact with both amyloid-β (Aβ, associated with Alzheimer disease) and hIAPP (associated with type II diabetes), thus promoting their amyloid aggregation process. At equal molar ratio, GNNQQNY promoted the fibrillation of both Aβ42 and hIAPP37 by reducing the lag-phase time up to 50%-75% and increasing fibril formation up to 150%-200%. Such GNNQQNY-induced acceleration of amyloid formation allows to rapidly bypass or convert toxic amyloid oligomers into less toxic amyloid fibrils, as evidenced by protecting neuroblastoma (SH-SY5Y) and insulinoma cells (INS-1) from Aβ42- and hIAPP37-induced toxicity with the cell viability increased by 56%-85%. Further molecular dynamics simulations revealed the GNNQQNY presented a high tendency to interact with the two-terminal tails of Aβ and N-terminal tails of hIAPP residues in an antiparallel packing pattern, thus promoting the antiparallel β-sheet stackings. Taken together, GNNQQNY demonstrates its dual cross-seeding ability to facilitate Aβ and hIAPP aggregation and to reduce Aβ- and hIAPP-induced cell toxicity, which offer a new design strategy for amyloid inhibitors against different PMDs and a better understanding of cross-seeding mechanisms linked to different PMDs.

GNNQQNY as a dual cross-seeding peptide to promote amyloid fibrillation of both amyloid-β and hIAPP

ACS Fall 2020 Virtual Meeting

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