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

• Published in: Protein science Vol. 31; no. 2; pp. 485 - 497
• Main Authors: Tang, Yijing, Zhang, Dong, Liu, Yonglan, Zhang, Yanxian, Zhou, Yifan, Chang, Yung, Zheng, Bowen, Xu, Alice, Zheng, Jie
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.02.2022; Wiley Subscription Services, Inc
• Subjects: Agglomeration; alpha-Synuclein - chemistry; Amyloid - chemistry; amyloid aggregation; Amyloid beta-Peptides - chemistry; amyloid cross‐seeding; Amyloidogenic Proteins - chemistry; Apoptosis; Cell viability; Cytotoxicity; Diabetes mellitus (non-insulin dependent); Fibrillogenesis; Fibrils; Full‐Length Paper; Full‐Length Papers; hIAPP; Humans; Islet Amyloid Polypeptide - chemistry; Modulators; Monomers; Movement disorders; Neurodegenerative Diseases; Neuromodulation; Parkinson disease; Parkinson's disease; Protein seeding; Proteins; Synuclein; Toxicity; Type 2 diabetes; α‐synuclein; β-Amyloid; Type 2 diabetes; Parkinson disease; amyloid aggregation; hIAPP; α-synuclein; amyloid cross-seeding
• ISSN: 0961-8368; 1469-896X; 1469-896X
• DOI: 10.1002/pro.4247

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 β‐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.