Expression of huntingtin and TDP-43 derivatives in fission yeast can cause both beneficial and toxic effects
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Marte, Luis, 1990-
- dc.contributor.author Boronat i Llop, Susanna, 1965-
- dc.contributor.author Barrios, Rubén
- dc.contributor.author Barcons-Simon, Anna
- dc.contributor.author Bolognesi, Benedetta
- dc.contributor.author Cabrera, Margarita
- dc.contributor.author Ayté del Olmo, José
- dc.contributor.author Hidalgo Hernando, Elena
- dc.date.accessioned 2022-06-14T06:00:52Z
- dc.date.available 2022-06-14T06:00:52Z
- dc.date.issued 2022
- dc.description.abstract Many neurodegenerative disorders display protein aggregation as a hallmark, Huntingtin and TDP-43 aggregates being characteristic of Huntington disease and amyotrophic lateral sclerosis, respectively. However, whether these aggregates cause the diseases, are secondary by-products, or even have protective effects, is a matter of debate. Mutations in both human proteins can modulate the structure, number and type of aggregates, as well as their toxicity. To study the role of protein aggregates in cellular fitness, we have expressed in a highly tractable unicellular model different variants of Huntingtin and TDP-43. They each display specific patterns of aggregation and toxicity, even though in both cases proteins have to be very highly expressed to affect cell fitness. The aggregation properties of Huntingtin, but not of TDP-43, are affected by chaperones such as Hsp104 and the Hsp40 couple Mas5, suggesting that the TDP-43, but not Huntingtin, derivatives have intrinsic aggregation propensity. Importantly, expression of the aggregating form of Huntingtin causes a significant extension of fission yeast lifespan, probably as a consequence of kidnapping chaperones required for maintaining stress responses off. Our study demonstrates that in general these prion-like proteins do not cause toxicity under normal conditions, and in fact they can protect cells through indirect mechanisms which up-regulate cellular defense pathways.
- dc.description.sponsorship This work is supported by grant PGC2018-093920-B-I00 to E.H, funded by MCINN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe”, by the “European Union”. The Oxidative Stress and Cell Cycle group is also supported by Generalitat de Catalunya (Spain) (2017-SGR-539) and by Excellence Unit «María de Maeztu» Grant CEX2018-000792-M funded by MCIN/AEI/10.13039/501100011033. E.H. is recipient of an ICREA Academia Award (Generalitat de Catalunya, Spain).
- dc.format.mimetype application/pdf
- dc.identifier.citation Marte L, Boronat S, Barrios R, Barcons-Simon A, Bolognesi B, Cabrera M, Ayté J, Hidalgo E. Expression of huntingtin and TDP-43 derivatives in fission yeast can cause both beneficial and toxic effects. Int J Mol Sci. 2022 Apr 1;23(7):3950. DOI: 10.3390/ijms23073950
- dc.identifier.doi http://dx.doi.org/10.3390/ijms23073950
- dc.identifier.issn 1422-0067
- dc.identifier.uri http://hdl.handle.net/10230/53478
- dc.language.iso eng
- dc.publisher MDPI
- dc.relation.ispartof Int J Mol Sci. 2022 Apr 1;23(7):3950
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-093920-B-I00
- dc.rights © 2022 by the authors. 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/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri https://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword TDP-43
- dc.subject.keyword Fission yeast
- dc.subject.keyword Huntingtin
- dc.subject.keyword Neurodegenerative diseases
- dc.subject.keyword Protein aggregation
- dc.title Expression of huntingtin and TDP-43 derivatives in fission yeast can cause both beneficial and toxic effects
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion