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Single-Molecular Heteroamyloidosis of Human Islet Amyloid Polypeptide
- Source :
- Nano Lett
- Publication Year :
- 2019
-
Abstract
- Human amyloids and plaques uncovered post mortem are highly heterogeneous in structure and composition, yet literature concerning the hetero-aggregation 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 co-aggregation 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 co-aggregation significantly prolonged the pause phase of fibril elongation, increasing its dwell time by threefold. Surprisingly, unidirectional elongation of mature fibrils, instead of protofilaments, was observed for the co-aggregation, 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 hetero-aggregates 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.
- Subjects :
- Amyloid
Bioengineering
Peptide
02 engineering and technology
Protein aggregation
Fibril
Microscopy, Atomic Force
Protein Aggregation, Pathological
Article
Microscopy, Electron, Transmission
In vivo
Animals
Humans
General Materials Science
Zebrafish
chemistry.chemical_classification
geography
geography.geographical_feature_category
biology
Mechanical Engineering
General Chemistry
Amyloidosis
021001 nanoscience & nanotechnology
Condensed Matter Physics
biology.organism_classification
Islet
Embryonic stem cell
Cell biology
Islet Amyloid Polypeptide
Disease Models, Animal
chemistry
Diabetes Mellitus, Type 2
0210 nano-technology
Subjects
Details
- ISSN :
- 15306992
- Volume :
- 19
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Nano letters
- Accession number :
- edsair.doi.dedup.....9dfe3b207366cf3ca73195d4e9f2ecb1