UC San Diego

Protein aggregation is a hallmark of aging and age-related diseases. Meanwhile, physiological aggregation of proteins and other bio-molecules is used by cells as a strategy to maintain cellular fitness under various conditions. RNA-binding proteins, possibly due to their intrinsically disordered and aggregation-prone nature, are associated with many pathological and physiological aggregates. Here we examine the subcellular localization of a group of proteins from two mRNP structures during yeast replicative aging by fluorescence microscopy. We find that several P-body components form an aggregate during aging in yeast. This P-body-like aggregate differs from normal yeast P-bodies in its insensitivity to glucose starvation and the absence of certain mRNA species. Similar to yeast P-bodies, it has a relatively dynamic structure, which can be disrupted by hexanediol treatment and upon the inhibition of protein translation. Furthermore, the aggregate does not contain protein disaggregase Hsp104, a marker for misfolded protein inclusions, under different conditions and thus unlikely to be a physiological deposition site of misfolded proteins. Combining several lines of evidence, we speculate that the age-related P-body-like aggregate represents an aberrant state of P-bodies with altered composition and function. We propose that fully understanding its formation and function in yeast will provide insights into mechanisms that underlie human aging and age-related diseases.