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 H Horrocks, Annalisa Pastore, Gian Gaetano Tartaglia

Research output: Contribution to journalArticlepeer-review

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
Pages (from-to)3306
JournalNature Communications
Volume13
Issue number1
Early online date23 Jun 2022
DOIs
Publication statusE-pub ahead of print - 23 Jun 2022

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