PROJECT SUMMARY This proposal is to examine the basis of intertissue signaling in the regulation of organismal proteostasis. We posit that tissue health is influenced by signals between peripheral tissues and neurons to establish an integrated proteostasis network (PN) in metazoans. This ensures that the proteome expressed by each tissue is engaged with its corresponding tissue PN for balanced synthesis, folding and function, and degradation. In addition to coordinating proteome health within each tissue, intertissue signaling affects the organismal response to proteotoxicity during aging. Our previous work provided some of the key observations to suggest a role for peripheral proteostasis in C. elegans. We showed that the organismal heat shock response (HSR) is regulated by a specific sensory neuron that communicates the cell stress signal via serotonin to the somatic tissues, that an imbalance in proteostasis within any single tissue sends a stress response signal to peripheral receiving tissues resulting in a compensatory transcellular chaperone response, and that germ line stem cells regulate the HSR in peripheral somatic tissues at reproductive maturity using a global chromatin repression signal to initiate PN failure in aging. These studies provide the basis for this proposal to understand the regulation and properties of peripheral proteostasis. We propose the following Aims: (1) To establish the functional properties of the tissue PN in neurons, body wall muscle cells, and intestine of C. elegans, (2) To identify the signaling pathways for communication between neurons, body wall muscle cells, and intestine for peripheral proteostasis, and (3) To examine how proteotoxic proteins Abeta, tau or polyQ affects peripheral proteostasis, and the effects of aging on aggregation and toxicity.