Adaptive inter-tissue proteostasis networks in aging and neurodegeneration

The maintenance of proteostasis is essential for cellular function and organismal health. Its decline with age is a key contributor to neurodegenerative diseases, metabolic disorders, and other chronic conditions. Eukaryotic cells respond to proteotoxic stress through compartment-specific pathways, including the heat shock response (HSR), the unfolded protein response of the endoplasmic reticulum (UPRER), and the mitochondrial UPR (UPRmt). While these pathways have been extensively studied in cell-autonomous contexts, recent evidence reveals that neurons and glial cells can co-ordinate these responses across tissues through cell-non-autonomous mechanisms. Neuronal signals, including neuropeptides, biogenic amines, and possibly extracellular vesicles, can activate stress responses in distal cells, modulating lipid metabolism and impacting longevity. Emerging data also suggest a role for glial cells in systemic proteostasis regulation, though their mechanisms remain relatively uncharacterized. This review discusses both classical and emerging concepts of proteostasis stress-response pathways, their integration with neural signaling, and how their modulation influences aging and disease. Understanding how intercellular communication governs proteostasis could open new avenues for therapeutic interventions in age-related and neurodegenerative disorders.