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

Itamar Harel ¹ Yiwen Chen ³ Inbal Ziv-Uziel ³ Param Priya Singh ² Uri Goshtchevsky ¹ Paloma Navarro Negredo ² Wei Wang ⁴ Gwendoline Astre ¹ Andrew Mckay ² Ben Machado ² Alejandro Sánchez Alvarado ⁴ Daniel Jarosz ³ Anne Brunet ²

¹Genetics, The Silberman Institute, the Hebrew University of Jerusalem, Givat Ram, Israel
²Genetics, Stanford University, USA
³Chemical and Systems Biology, Stanford University, USA
⁴Howard Hughes Medical Institute, Stowers Institute for Medical Research, USA

Protein aggregates can spread in a prion-like manner in neurodegenerative diseases. But whether prion-like properties are engaged in the brain during normal aging remains unknown. Here we use quantitative proteomics in the African killifish to identify protein aggregates that accumulate with age in the vertebrate brain. Interestingly, proteins that aggregate with age are enriched for prion-like domains, and they include the RNA helicase DDX5. We verify that DDX5 forms cytoplasmic aggregates in the brains of old killifish and aged mice. Surprisingly, DDX5 aggregates act as bona fide prions that propagate across many generations in yeast. In vitro, DDX5 aggregate seeding occurs in a protein-autonomous manner, with phase-separation into a droplet-like structure. Mutations that impair the ability of DDX5 to phase-separate also affect prion-like properties in cells. Thus, protein aggregates with prion-like properties can form during normal aging, and their phase-separation properties could contribute to the age-dependency of cognitive decline.