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Compositional Control of Aging Kinetics in TDP-43 Condensates

Nuria H. Espejo1,2,*, Alejandro Feito1,*, Ignacio Sanchez-Burgos3, Adiran Garaizar2, Maria M. Conde4, Antonio Rey1, Eduardo Pedraza1, Alejandro Castro1, Rosana Collepardo-Guevara3 et al.

Andres R. Tejedor1,3,‡ and Jorge R. Espinosa1,3,†

  • *These authors contributed equally to this work.
  • †Contact author: jorgerene@ucm.es
  • ‡Contact author: at949@cam.ac.uk
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PRX Life 3, 043018 – Published 11 December, 2025

DOI: https://doi.org/10.1103/w7g3-6rsd

Abstract

The spontaneous self-assembly of proteins and nucleic acids into biomolecular condensates has been shown to ubiquitously contribute to the functional compartmentalization of the cell. However, their liquid-to-solid transformation (i.e., aging) driven by interprotein β-sheet transitions represents a hallmark of multiple neurodegenerative disorders. We perform molecular dynamics simulations to elucidate the role of different biomolecules in regulating the aging kinetics of TDP-43, an RNA-binding protein linked to amyotrophic lateral sclerosis and frontotemporal dementia. We find that while arginine-rich peptides accelerate the nucleation of interprotein β-sheet structures, the inclusion of RNAs and the HSP70 chaperone slows down their emergence. Interestingly, we observe a correlation between the protein compactness—governed by the condensate composition—and aging kinetics. Moreover, we find that near-interfacial regions of TDP-43 condensates exhibit faster interprotein transitions than the core of the condensate. Together, our findings underscore the major role of client biomolecules in controlling the propensity of multicomponent condensates to form harmful solidlike states.

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Collection on Physics of Biomolecular Condensates

From the fundamentals of phase separation, dynamics and structure of condensates in biological settings, to advanced imaging methods, this special collection presented by PRX Life showcases exciting and timely work on the physics of biomolecular condensates.

This Invited Collection is coordinated by PRX Life Associate Editor Christoph Weber, in consultation with Jerelle Joseph, Simon Alberti, and Tanja Mittag. Every article published in this collection underwent a rigorous peer review process, adhering to the same high standards applied to all papers handled by the journal. The PRX Life editorial team managed the peer review and made all editorial decisions.

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PRX Life 3, 043018– Published 11 December, 2025
  • Received 17 March 2025
  • Accepted 7 October 2025
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