A comparative meta-analysis of membraneless organelle-associated proteins with age related proteome of C. elegans.

Abstract

Proteome imbalance can lead to protein misfolding and aggregation which is associated with pathologies. Protein aggregation can also be an active, organized process and can be exploited by cells as a survival strategy. In adverse conditions, it is beneficial to deposit the proteins in a condensate rather degrading and resynthesizing. Membraneless organelles (MLOs) are biological condensates formed through liquid-liquid phase separation (LLPS), involving cellular components such as nucleic acids and proteins. LLPS is a regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates. To understand how the MLO-associated proteins (MLO-APs) behave during aging, we performed a comparative meta-analysis with age-related proteome of C. elegans. We found that the MLO-APs are highly abundant throughout the lifespan in wild-type and long-lived daf-2 mutant animals. Interestingly, they are aggregating more in long-lived mutant animals compared to the age matched wild-type and short-lived daf-16 and hsf-1 mutant animals. GO term analysis revealed that the cell cycle and embryonic development are among the top enriched processes in addition to RNP components in aggregated proteome. Considering antagonistic pleotropic nature of these developmental genes and post mitotic status of C. elegans, we assume that these proteins phase transit during post development. As the organism ages, these MLO-APs either mature to become more insoluble or dissolve in uncontrolled manner. However, in the long-lived daf-2 mutant animals, the MLOs may attain protective states due to extended availability and association of molecular chaperones.