Projects per year
Abstract
Human amyloids and plaques uncovered post mortem are highly heterogeneous in structure and composition, yet literature concerning the heteroaggregation of amyloid proteins is extremely scarce. This knowledge deficiency is further exacerbated by the fact that peptide delivery is a major therapeutic strategy for targeting their full-length counterparts associated with the pathologies of a range of human diseases, including dementia and type 2 diabetes (T2D). Accordingly, here we examined the coaggregation of full-length human islet amyloid polypeptide (IAPP), a peptide associated with type 2 diabetes, with its primary and secondary amyloidogenic fragments 19-29 S20G and 8-20. Single-molecular aggregation dynamics was obtained by high-speed atomic force microscopy, augmented by transmission electron microscopy, X-ray diffraction, and super-resolution stimulated emission depletion microscopy. The coaggregation significantly prolonged the pause phase of fibril elongation, increasing its dwell time by 3-fold. Surprisingly, unidirectional elongation of mature fibrils, instead of protofilaments, was observed for the coaggregation, indicating a new form of tertiary protein aggregation unknown to existing theoretical models. Further in vivo zebrafish embryonic assay indicated improved survival and hatching, as well as decreased frequency and severity of developmental abnormalities for embryos treated with the heteroaggregates of IAPP with 19-29 S20G, but not with 8-20, compared to the control, indicating the therapeutic potential of 19-29 S20G against T2D.
Original language | English |
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Pages (from-to) | 6535-6546 |
Number of pages | 12 |
Journal | Nano Letters |
Volume | 19 |
Issue number | 9 |
DOIs | |
Publication status | Published - 11 Sept 2019 |
Keywords
- fibrillization dynamics
- fragment
- heteroaggregation
- high-speed atomic force microscopy
- IAPP
Projects
- 2 Finished
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ARC Centre of Excellence in Convergent Bio-Nano Science and Technology
Davis, T. (Primary Chief Investigator (PCI)), Boyd, B. (Chief Investigator (CI)), Bunnett, N. (Chief Investigator (CI)), Porter, C. (Chief Investigator (CI)), Caruso, F. (Chief Investigator (CI)), Kent, S. (Chief Investigator (CI)), Thordarson, P. (Chief Investigator (CI)), Kearnes, M. (Chief Investigator (CI)), Gooding, J. (Chief Investigator (CI)), Kavallaris, M. (Chief Investigator (CI)), Thurecht, K. J. (Chief Investigator (CI)), Whittaker, A. K. (Chief Investigator (CI)), Parton, R. (Chief Investigator (CI)), Corrie, S. R. (Chief Investigator (CI)), Johnston, A. (Chief Investigator (CI)), McGhee, J. (Chief Investigator (CI)), Greguric, I. D. (Partner Investigator (PI)), Stevens, M. M. (Partner Investigator (PI)), Lewis, J. S. (Partner Investigator (PI)), Lee, D. S. (Partner Investigator (PI)), Alexander, C. (Partner Investigator (PI)), Dawson, K. (Partner Investigator (PI)), Hawker, C. (Partner Investigator (PI)), Haddleton, D. (Partner Investigator (PI)), Thierry, B. (Chief Investigator (CI)), Prestidge, C. A. (Chief Investigator (CI)), Meyer, A. (Project Manager), Jones-Jayasinghe, N. (Project Manager), Voelcker, N. (Chief Investigator (CI)), Nann, T. (Chief Investigator (CI)) & McLean, K. (Partner Investigator (PI))
Australian Research Council (ARC), Monash University, University of Melbourne, University of New South Wales (UNSW), University of Queensland , University of South Australia, Monash University – Internal Faculty Contribution, University of Wisconsin Madison, Memorial Sloan Kettering Cancer Center, University of California System, University College Dublin, Imperial College London, University of Warwick, Sungkyunkwan University, Australian Nuclear Science and Technology Organisation (ANSTO) , University of Nottingham
30/06/14 → 29/06/21
Project: Research
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ARC Centre of Excellence for Electromaterials Science
Wallace, G. G. (Primary Chief Investigator (PCI)), Forsyth, M. (Chief Investigator (CI)), Macfarlane, D. (Chief Investigator (CI)), Officer, D. (Chief Investigator (CI)), Cook, M. J. (Chief Investigator (CI)), Dodds, S. (Chief Investigator (CI)), Spinks, G. (Chief Investigator (CI)), Alici, G. (Chief Investigator (CI)), Moulton, S. (Chief Investigator (CI)), in het Panhuis, M. (Chief Investigator (CI)), Kapsa, R. M. I. (Chief Investigator (CI)), Higgins, M. (Chief Investigator (CI)), Mozer, A. (Chief Investigator (CI)), Crook, J. (Chief Investigator (CI)), Innis, P. (Chief Investigator (CI)), Coote, M. L. (Chief Investigator (CI)), Wang, X. (Chief Investigator (CI)), Howlett, P. C. (Chief Investigator (CI)), Pringle, J. (Chief Investigator (CI)), Hancock, L. (Chief Investigator (CI)), Paull, B. (Chief Investigator (CI)), Sparrow, R. (Chief Investigator (CI)), Zhang, J. (Chief Investigator (CI)), Spiccia, L. (Chief Investigator (CI)), Diamond, D. (Partner Investigator (PI)), Guldi, D. (Partner Investigator (PI)), Kim, S. J. (Partner Investigator (PI)), Unwin, P. (Partner Investigator (PI)) & Watanabe, M. (Partner Investigator (PI))
Australian Research Council (ARC)
30/06/14 → 30/06/21
Project: Research
Equipment
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Monash Micro Imaging (MMI)
Firth, S. (Manager), Fulcher, A. (Operator), Chernyavskiy, O. (Operator), Rzeszutek, M. (Other), Potter, D. (Manager), Hilsenstein, V. (Operator), Nunez-Iglesias, J. (Other), Cody, S. (Manager), Carmichael, I. (Operator), Kouskousis, B. (Other), Creed, S. (Manager) & Ballerin, G. (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility