Probing TDP-43 condensation using an in silico designed aptamer

Elsa Zacco, Owen Kantelberg, Edoardo Milanetti, Alexandros Armaos, Francesco Paolo Panei, Jenna Gregory, Kiani Jeacock, David J. Clarke, Siddharthan Chandran, Giancarlo Ruocco, Stefano Gustincich, Mathew Horrocks* (Corresponding Author), Annalisa Pastore* (Corresponding Author), Gian Gaetano Tartaglia* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.
Original languageEnglish
Article number3306
Number of pages13
JournalNature Communications
Volume13
DOIs
Publication statusPublished - 23 Jun 2022

Keywords

  • computational models
  • RNA
  • RNA-Binding Proteins
  • Super-resolution microscopy

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