Protein Aggregates With Prion-Like Properties In The Aging Vertebrate Brain - Genome Dynamics in Neuroscience and Aging

Itamar Harel ^1,2 Yiwen Chen ³ Yiwen Chen Inbal Ziv-Uziel ³ Katja Hebestreit ² Inbal Ziv-Uziel Param Priya Singh ² Daniel Jarosz ³ Anne Brunet ²

¹Department of Genetics, The Hebrew University of Jerusalem, Israel
²Department of Genetics, Stanford University, USA
³Department of Chemical and Systems Biology, Stanford University, USA

Protein aggregation is a hallmark of many age-dependent neurodegenerative diseases, and some disease-associated protein aggregates can spread in a prion-like manner. Yet whether prion-like properties are engaged in the brain during normal vertebrate aging remains unknown. Here we leverage the naturally short-lived African turquoise killifish as a powerful vertebrate model to identify protein aggregates that accumulate with age in the brain. Interestingly, we find that the proteins that aggregate with age are enriched for the presence of prion-like domains. These include many RNA binding proteins such as the RNA helicase DDX5, which forms cytoplasmic aggregates in old brains. Using a yeast model, we show that DDX5 aggregates act as bona fide prions that propagate across many generations. In vitro, DDX5 aggregate seeding occurs in a protein-autonomous manner. In-vitro, we further characterize specific DDX5 mutants in which aggregation propensity is uncoupled from prion-like propagation properties. These data indicate that protein aggregates with prion-like properties form during normal aging, and further suggest these properties could contribute to the age dependency of neurodegenerative diseases.