Cargando…
The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells
Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncov...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234475/ https://www.ncbi.nlm.nih.gov/pubmed/34205516 http://dx.doi.org/10.3390/molecules26123760 |
_version_ | 1783714092630933504 |
---|---|
author | González, Camila Cartagena, Constanza Caballero, Leonardo Melo, Francisco Areche, Carlos Cornejo, Alberto |
author_facet | González, Camila Cartagena, Constanza Caballero, Leonardo Melo, Francisco Areche, Carlos Cornejo, Alberto |
author_sort | González, Camila |
collection | PubMed |
description | Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael’s addition appears as a feasible type of interaction involving an α, β unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish β sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael’s acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species. |
format | Online Article Text |
id | pubmed-8234475 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82344752021-06-27 The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells González, Camila Cartagena, Constanza Caballero, Leonardo Melo, Francisco Areche, Carlos Cornejo, Alberto Molecules Article Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael’s addition appears as a feasible type of interaction involving an α, β unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish β sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael’s acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species. MDPI 2021-06-21 /pmc/articles/PMC8234475/ /pubmed/34205516 http://dx.doi.org/10.3390/molecules26123760 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article González, Camila Cartagena, Constanza Caballero, Leonardo Melo, Francisco Areche, Carlos Cornejo, Alberto The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells |
title | The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells |
title_full | The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells |
title_fullStr | The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells |
title_full_unstemmed | The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells |
title_short | The Fumarprotocetraric Acid Inhibits Tau Covalently, Avoiding Cytotoxicity of Aggregates in Cells |
title_sort | fumarprotocetraric acid inhibits tau covalently, avoiding cytotoxicity of aggregates in cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234475/ https://www.ncbi.nlm.nih.gov/pubmed/34205516 http://dx.doi.org/10.3390/molecules26123760 |
work_keys_str_mv | AT gonzalezcamila thefumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT cartagenaconstanza thefumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT caballeroleonardo thefumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT melofrancisco thefumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT arechecarlos thefumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT cornejoalberto thefumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT gonzalezcamila fumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT cartagenaconstanza fumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT caballeroleonardo fumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT melofrancisco fumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT arechecarlos fumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells AT cornejoalberto fumarprotocetraricacidinhibitstaucovalentlyavoidingcytotoxicityofaggregatesincells |