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

Authors :
Itamar Harel
Yiwen R. Chen
Inbal Ziv
Param Priya Singh
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
Publication Year :
2022
Publisher :
Cold Spring Harbor Laboratory, 2022.

Abstract

SUMMARYProtein 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 mislocalized cytoplasmic aggregates 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........3ca9c6523399e065b414dcc28a0b4e91
Full Text :
https://doi.org/10.1101/2022.02.26.482115