A new strategy to reconcile amyloid cross-seeding and amyloid prevention in a binary system of α-synuclein fragmental peptide and hIAPP.

ABSTRACT

Amyloid cross-seeding and amyloid inhibition are two different research subjects being studied separately for different pathological purposes, in which amyloid cross-seeding targets to study the co-aggregation of different amyloid proteins and potential molecular links between different neurodegenerative diseases, while amyloid inhibition aims to design different molecules for preventing amyloid aggregation. While both amyloid cross-seeding and amyloid inhibition are critical for better understanding the pathological causes of different neurodegenerative diseases including Parkinson disease (PD) and Type 2 diabetes (T2D), less efforts have been made to reconcile the two phenomena. Herein, we proposed a new preventive strategy to demonstrate (a) the cross-seeding of octapeptide TKEQVTNV from α-synuclein (associated with PD) with hIAPP (associated with T2D) and (b) the cross-seeding-promoted hIAPP fibrillization and cross-seeding-reduced hIAPP toxicity. Collective results confirmed that TKEQVTNV can indeed cross-seed with hIAPP monomers and oligomers, not protofibrils, to form ß-structure-rich fibrils and to accelerate hIAPP fibrillization. Moreover, such cross-seeding-induced promotion effect by TKEQVTNV also rescued the pancreatic cells from hIAPP-induced cytotoxicity by increasing cell viability and reducing cell apoptosis simultaneously. This work provides a new angle to discover amyloid fragments and use them as amyloid modulators (inhibitors or promotors) to interfere with amyloid aggregation of other amyloid proteins, as well as sequence/structure basis to explore the amyloid cross-seeding between different amyloid proteins that may help explain a potential molecular talk between different neurodegenerative diseases.