DDX5 Can Form Prion-Like Aggregates in the Aging Brain

A prion is a protein that can misfold in a way that encourages other molecules of the same protein to misfold in the same way. It can thus spread like a pathogen through cells and tissues, producing pathological changes in its wake. "Prion" is a term used inconsistently in the research community, as the very well researched amyloid-β and α-synuclein, drivers of neurodegenerative conditions, have prion-like properties but are rarely referred to as prions. So in one sense, yes, there are indeed prions in the aging brain, spreading and causing harm. Here, researchers look into the protein DDX5 in short-lived killifish, and report that it, too, can exhibit prion-like behavior and thus may be causing harm in the aging brain. As they note, the human version of this gene is very similar, similar enough that the observations may hold up in our species.

Prion-like properties have been proposed to drive the progression of several neurodegenerative pathologies by facilitating the transmission of protein aggregates from affected to unaffected areas of the brain. Long viewed as a rare biological oddity, prions have recently been discovered throughout evolution, from yeast to humans. Prions and prion-like self-assembly have been implicated in normal physiological functions, such as metabolism, cell fate determination, antiviral responses, and inflammation.

Here, we leverage the killifish as a powerful model to unbiasedly identify proteins that aggregate during normal brain aging. Using quantitative proteomics, we identify many proteins with an increased propensity to aggregate in the aging brain. One of these proteins, the RNA helicase DDX5, forms aggregate-like puncta in old brains of both killifish and mice and has prion-like seeding properties in cells. DDX5 rapidly undergoes phase separation in vitro, and these condensates mature into solid aggregates that are inactive and potentially infectious. The aggregation of key proteins during normal vertebrate brain aging could contribute to the age dependency of cognitive decline.

Link: https://doi.org/10.1016/j.celrep.2023.112787

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