Cargando…
The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrP(Sc)) which forms amyloid plaques leading to fatal neurodegeneration. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Herein, we report novel...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037109/ https://www.ncbi.nlm.nih.gov/pubmed/35479435 http://dx.doi.org/10.1039/d1ra01891d |
_version_ | 1784693661564403712 |
---|---|
author | Sirohi, Preeti Rana Kumari, Anchala Admane, Nikita Somvanshi, Pallavi Grover, Abhinav |
author_facet | Sirohi, Preeti Rana Kumari, Anchala Admane, Nikita Somvanshi, Pallavi Grover, Abhinav |
author_sort | Sirohi, Preeti Rana |
collection | PubMed |
description | Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrP(Sc)) which forms amyloid plaques leading to fatal neurodegeneration. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Herein, we report novel prion intervention by the polyphenolic phytoalexin, polydatin which binds with moderate affinity to the recombinant protease resistant core of human prion protein, encompassing the sequence 90–231 (rPrP(res)) and inhibits its conversion into the highly neurotoxic forms. An extensive evaluation using biophysical techniques revealed that polydatin incubated rPrP(res) samples generate off-pathway oligomers having reduced cross-β sheet signature, and relatively smaller in size than the native rPrP(res) oligomers. The detailed structural analysis using molecular dynamics simulations elucidated the induction of antagonistic mobilities in the β2–α2 loop, α3 helix and the N-terminal amyloidogenic region of prions. This study puts forward novel prion fibrillogenesis inhibitory potential of polydatin, specifically by stabilizing the N-terminal amyloidogenic region. Collectively our results affirm the importance of polydatin in crippling the prion pathogenesis and may serve as a structural scaffold for designing novel therapeutic agents targeting amyloidogenic transition in prions. |
format | Online Article Text |
id | pubmed-9037109 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-90371092022-04-26 The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein Sirohi, Preeti Rana Kumari, Anchala Admane, Nikita Somvanshi, Pallavi Grover, Abhinav RSC Adv Chemistry Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrP(Sc)) which forms amyloid plaques leading to fatal neurodegeneration. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Herein, we report novel prion intervention by the polyphenolic phytoalexin, polydatin which binds with moderate affinity to the recombinant protease resistant core of human prion protein, encompassing the sequence 90–231 (rPrP(res)) and inhibits its conversion into the highly neurotoxic forms. An extensive evaluation using biophysical techniques revealed that polydatin incubated rPrP(res) samples generate off-pathway oligomers having reduced cross-β sheet signature, and relatively smaller in size than the native rPrP(res) oligomers. The detailed structural analysis using molecular dynamics simulations elucidated the induction of antagonistic mobilities in the β2–α2 loop, α3 helix and the N-terminal amyloidogenic region of prions. This study puts forward novel prion fibrillogenesis inhibitory potential of polydatin, specifically by stabilizing the N-terminal amyloidogenic region. Collectively our results affirm the importance of polydatin in crippling the prion pathogenesis and may serve as a structural scaffold for designing novel therapeutic agents targeting amyloidogenic transition in prions. The Royal Society of Chemistry 2021-07-28 /pmc/articles/PMC9037109/ /pubmed/35479435 http://dx.doi.org/10.1039/d1ra01891d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Sirohi, Preeti Rana Kumari, Anchala Admane, Nikita Somvanshi, Pallavi Grover, Abhinav The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein |
title | The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein |
title_full | The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein |
title_fullStr | The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein |
title_full_unstemmed | The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein |
title_short | The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein |
title_sort | polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037109/ https://www.ncbi.nlm.nih.gov/pubmed/35479435 http://dx.doi.org/10.1039/d1ra01891d |
work_keys_str_mv | AT sirohipreetirana thepolyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT kumarianchala thepolyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT admanenikita thepolyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT somvanshipallavi thepolyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT groverabhinav thepolyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT sirohipreetirana polyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT kumarianchala polyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT admanenikita polyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT somvanshipallavi polyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein AT groverabhinav polyphenolicphytoalexinpolydatininhibitsamyloidaggregationofrecombinanthumanprionprotein |