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 () and Gian Gaetano Tartaglia ()
Additional contact information
Elsa Zacco: Istituto Italiano di Tecnologia (IIT)
Owen Kantelberg: University of Edinburgh
Edoardo Milanetti: Sapienza University
Alexandros Armaos: Istituto Italiano di Tecnologia (IIT)
Francesco Paolo Panei: Sapienza University
Jenna Gregory: University of Edinburgh, Edinburgh bioQuarter
Kiani Jeacock: University of Edinburgh
David J. Clarke: University of Edinburgh
Siddharthan Chandran: University of Edinburgh, Edinburgh bioQuarter
Giancarlo Ruocco: Sapienza University
Stefano Gustincich: Istituto Italiano di Tecnologia (IIT)
Mathew H. Horrocks: University of Edinburgh
Annalisa Pastore: UK Dementia Research Institute at the Maurice Wohl Institute of King’s College London
Gian Gaetano Tartaglia: Istituto Italiano di Tecnologia (IIT)

Nature Communications, 2022, vol. 13, issue 1, 1-13

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.

Date: 2022
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DOI: 10.1038/s41467-022-30944-x

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