Probing TDP-43 condensation using an in silico designed aptamer

Mostra el registre complet Registre parcial de l'ítem

  • dc.contributor.author Zacco, Elsa
  • dc.contributor.author Kantelberg, Owen
  • dc.contributor.author Milanetti, Edoardo
  • dc.contributor.author Armaos, Alexandros, 1989-
  • dc.contributor.author Panei, Francesco Paolo
  • dc.contributor.author Gregory, Jenna
  • dc.contributor.author Jeacock, Kiani
  • dc.contributor.author Clarke, David J.
  • dc.contributor.author Chandran, Siddharthan
  • dc.contributor.author Ruocco, Giancarlo
  • dc.contributor.author Gustincich, Stefano
  • dc.contributor.author Horrocks, Mathew H.
  • dc.contributor.author Pastore, Annalisa
  • dc.contributor.author Tartaglia, Gian Gaetano
  • dc.date.accessioned 2022-11-07T07:30:03Z
  • dc.date.available 2022-11-07T07:30:03Z
  • dc.date.issued 2022
  • dc.description.abstract Aptamers are artificial oligonucleotides binding to specific molecular targets. They have a promising role in therapeutics and diagnostics but are often difficult to design. Here, we exploited the catRAPID algorithm to generate aptamers targeting TAR DNA-binding protein 43 (TDP-43), whose aggregation is associated with Amyotrophic Lateral Sclerosis. On the pathway to forming insoluble inclusions, TDP-43 adopts a heterogeneous population of assemblies, many smaller than the diffraction-limit of light. We demonstrated that our aptamers bind TDP-43 and used the tightest interactor, Apt-1, as a probe to visualize TDP-43 condensates with super-resolution microscopy. At a resolution of 10 nanometers, we tracked TDP-43 oligomers undetectable by standard approaches. In cells, Apt-1 interacts with both diffuse and condensed forms of TDP-43, indicating that Apt-1 can be exploited to follow TDP-43 phase transition. The de novo generation of aptamers and their use for microscopy opens a new page to study protein condensation.
  • dc.description.sponsorship We thank the “RNA Initiative” at IIT, all members of the M.H.H., A.P., and G.G.T. groups, and especially Fernando Cid Samper. M.H.H. wishes to thank UCB Biopharma and Dr Jim Love for providing funding for the instrument used to generate the super-resolution data in this manuscript. A.P. acknowledges funding from UK DRI (grant REI 3556) and AlzheimerUK (grant ARUK-PG2019B-020). O.K. was supported by a Scottish PhD Research & Innovation Network Traineeships in MND/MS. E.Z. received funding from the Newton fellowship scheme and the MINDED fellowship of the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 754490. K.J. was funded via the BBSRCEastBIO doctoral training program (BB/M010996/1). The research leading to these results was supported by European Research Council [RIBOMYLOME n. 309545 to G.G.T. and ASTRA n. 855923 to G.G.T.], H2020 [IASIS n. 727658 to G.G.T. and INFORE n. 825080 to G.G.T.] and MND [840-791 to G.G.T. and A.P.] projects. The authors would also like to acknowledge the help and support received during confocal images acquisition by the group of Giuseppe Vicidomini at the Molecular Microscopy and Spectroscopy Department of IIT.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Zacco E, Kantelberg O, Milanetti E, Armaos A, Panei FP, Gregory J, Jeacock K, Clarke DJ, Chandran S, Ruocco G, Gustincich S, Horrocks MH, Pastore A, Tartaglia GG. Probing TDP-43 condensation using an in silico designed aptamer. Nat Commun. 2022 Jun 23;13(1):3306. DOI: 10.1038/s41467-022-30944-x
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-30944-x
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/54717
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2022 Jun 23;13(1):3306
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/754490
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/855923
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/727658
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825080
  • dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Computational models
  • dc.subject.keyword RNA
  • dc.subject.keyword RNA-binding proteins
  • dc.subject.keyword Super-resolution microscopy
  • dc.title Probing TDP-43 condensation using an in silico designed aptamer
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)