RT Journal Article
SR Electronic
T1 Identification of protein aggregates in the aging vertebrate brain with prion-like and phase separation properties
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.26.482115
DO 10.1101/2022.02.26.482115
A1 Itamar Harel
A1 Yiwen R. Chen
A1 Inbal Ziv
A1 Param Priya Singh
A1 Paloma Navarro Negredo
A1 Uri Goshtchevsky
A1 Wei Wang
A1 Gwendoline Astre
A1 Eitan Moses
A1 Andrew McKay
A1 Ben E. Machado
A1 Katja Hebestreit
A1 Sifei Yin
A1 Alejandro Sánchez Alvarado
A1 Daniel F. Jarosz
A1 Anne Brunet
YR 2022
UL http://biorxiv.org/content/early/2022/03/01/2022.02.26.482115.abstract
AB 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 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.Competing Interest StatementThe authors have declared no competing interest.