Probing TDP-43 condensation using an in silico designed aptamer

Zacco, Elsa; Kantelberg, Owen; Milanetti, Edoardo; Armaos, Alexandros, 1989-; Panei, Francesco Paolo; Gregory, Jenna; Jeacock, Kiani; Clarke, David J.; Chandran, Siddharthan; Ruocco, Giancarlo; Gustincich, Stefano; Horrocks, Mathew H.; Pastore, Annalisa; Tartaglia, Gian Gaetano

doi:http://dx.doi.org/10.1038/s41467-022-30944-x

Probing TDP-43 condensation using an in silico designed aptamer

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Citación

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

Resumen

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.