Control of systemic proteostasis by the nervous system

• The proteostasis network mediates cellular adaptation to protein-folding stress.
• Cell-nonautonomous regulation of peripheral proteostasis is controlled by the central nervous system.
• Cell-nonautonomous control of proteostasis is implicated in thermoregulation, innate immunity, energy balance, and aging.
• Targeting the regulation of proteostasis by the nervous system has therapeutic potential.

Maintenance of organismal homeostasis depends on the integration of intracellular and external signals, involving the ability to detect molecular perturbations. An explosion of studies in model organisms indicates the occurrence of dynamic communication between alarm pathways engaged by protein-folding stress in neurons that activate adaptive programs in peripheral organs to control cellular proteostasis. Here we review emerging concepts that highlight the contribution of the proteostasis network to the regulation of several aspects of animal physiology through central integration of signals spanning multiple tissues and organs. These recent findings uncover a new layer of functional interrelation between cells that handle and orchestrate the global maintenance of the proteome at the organismal level in a cell-nonautonomous manner.