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.

Public Health Relevance

Among the most daunting diseases are those known as protein conformational diseases that cause neurodegeneration including Alzheimer's disease, Parkinson's disease, ALS and Huntington's disease. Each of these diseases and hundreds of others are due to protein aggregation and resulting tissue failure. This proposal is to address how different tissues communicate and coordinate the cellular response to aggregation and proteotoxicity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Special Emphasis Panel (ZAG1)
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Velazquez, Jose M
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Ciryam, Prajwal; Lambert-Smith, Isabella A; Bean, Daniel M et al. (2017) Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS. Proc Natl Acad Sci U S A 114:E3935-E3943
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Kirstein, Janine; Arnsburg, Kristin; Scior, Annika et al. (2017) In vivo properties of the disaggregase function of J-proteins and Hsc70 in Caenorhabditis elegans stress and aging. Aging Cell 16:1414-1424
Kundra, Rishika; Ciryam, Prajwal; Morimoto, Richard I et al. (2017) Protein homeostasis of a metastable subproteome associated with Alzheimer's disease. Proc Natl Acad Sci U S A 114:E5703-E5711