Single-Molecular Heteroamyloidosis of Human Islet Amyloid Polypeptide

Aleksandr Kakinen, Yanting Xing, Nuwan Hegoda Arachchi, Ibrahim Javed, Lei Feng, Ava Faridi, Alon M. Douek, Yunxiang Sun, Jan Kaslin, Thomas P. Davis, Michael J. Higgins, Feng Ding, Pu Chun Ke

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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 languageEnglish
Pages (from-to)6535-6546
Number of pages12
JournalNano Letters
Volume19
Issue number9
DOIs
Publication statusPublished - 11 Sep 2019

Keywords

  • fibrillization dynamics
  • fragment
  • heteroaggregation
  • high-speed atomic force microscopy
  • IAPP

Cite this

Kakinen, A., Xing, Y., Hegoda Arachchi, N., Javed, I., Feng, L., Faridi, A., Douek, A. M., Sun, Y., Kaslin, J., Davis, T. P., Higgins, M. J., Ding, F., & Ke, P. C. (2019). Single-Molecular Heteroamyloidosis of Human Islet Amyloid Polypeptide. Nano Letters, 19(9), 6535-6546. https://doi.org/10.1021/acs.nanolett.9b02771