Identification of protein aggregates in the aging vertebrate brain with prion-like and phase-separation properties

Itamar Harel*, Yiwen R. Chen, Inbal Ziv, Param Priya Singh, Daniel Heinzer, Paloma Navarro Negredo, Uri Goshtchevsky, Wei Wang, Gwendoline Astre, Eitan Moses, Andrew McKay, Ben E. Machado, Katja Hebestreit, Sifei Yin, Alejandro Sánchez Alvarado, Daniel F. Jarosz*, Anne Brunet*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Protein aggregation, which can sometimes spread in a prion-like manner, is a hallmark of neurodegenerative diseases. However, whether prion-like aggregates form during normal brain aging remains unknown. Here, we use quantitative proteomics in the African turquoise killifish to identify protein aggregates that accumulate in old vertebrate brains. These aggregates are enriched for prion-like RNA-binding proteins, notably the ATP-dependent RNA helicase DDX5. We validate that DDX5 forms aggregate-like puncta in the brains of old killifish and mice. Interestingly, DDX5’s prion-like domain allows these aggregates to propagate across many generations in yeast. In vitro, DDX5 phase separates into condensates. Mutations that abolish DDX5 prion propagation also impair the protein's ability to phase separate. DDX5 condensates exhibit enhanced enzymatic activity, but they can mature into inactive, solid aggregates. Our findings suggest that protein aggregates with prion-like properties form during normal brain aging, which could have implications for the age-dependency of cognitive decline.

Original languageEnglish
Article number112787
JournalCell Reports
Volume43
Issue number6
DOIs
StatePublished - 25 Jun 2024

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • CP: Cell biology
  • CP: Neuroscience
  • N. furzeri
  • aggregates
  • aging
  • killifish
  • phase separation

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