PROTEOSTASIS

The maintenance of proteome homeostasis (proteostasis) is essential for cellular health, survival, and longevity. Proteostatic mechanisms act as guardians of the proteome, ensuring its proper synthesis, maintenance, function, and clearance. Despite their importance, the regulation of these mechanisms and the molecular crosstalk between them is not fully understood. Clarifying these interactions would reveal the mechanisms by which mammals organize, maintain, and protect their proteome under normal conditions and under conditions of proteostasis collapse (e.g., diseases).

Although some proteostatic mechanisms have been extensively studied, knowledge regarding the interplay of the proteasome with stress response mechanisms, various molecular chaperones, and co-factors remains limited. Similarly, the effects of proteasome activation on cellular “surveillance” mechanisms—including the heat shock response (HSR), the mitochondrial unfolded protein response (UPR^mit), and the endoplasmic reticulum unfolded protein response (UPR^ER)—remain largely unexplored.

The objective of Proteostasis is to elucidate the molecular crosstalk mechanisms between the proteasome and other proteostatic pathways during aging, using the Caenorhabditis elegans model. Revealing the regulatory mechanisms involved in proteostasis in this lower organism will have significant implications for understanding many diseases associated with misfolded proteins and protein aggregates.

Furthermore, given that proteasome activation has been shown to increase cellular and organismal lifespan and delay the progression of protein-aggregation-related diseases (such as Alzheimer’s disease, AD), but genetic activation of the proteasome is not feasible in humans, the project also aims to identify natural metabolites from the Greek marine biodiversity that act as proteasome activators. Discovering natural dietary components may lead to the development of functional foods capable of preventing protein aggregation before aggregates become detectable but irreversible, offering a proactive strategy against proteotoxicity.