Compositional Control of Aging Kinetics in TDP-43 Condensates

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 <a:math xmlns:a="http://www.w3.org/1998/Math/MathML"> <a:mi>β</a:mi> </a:math> -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 <b:math xmlns:b="http://www.w3.org/1998/Math/MathML"> <b:mi>β</b:mi> </b:math> -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.