The health of the proteome is of central importance to the cell and contributes significantly to the health and lifespan of the organism. The proteome is constantly challenged by external physiological and environmental stress, and places demands upon the protein quality control machinery and the proteostasis network, to sense and respond to the expression of misfolded and damaged proteins. It is increasingly clear that acute proteotoxicity, associated with the chronic expression of disease-associated aggregation-prone proteins, is daunting to the cell. When proteostatic capacity is exceeded, the consequence can be neurodegeneration, cancer, immunological disease, or metabolic diseases. Our studies have shown that expression of an aggregation-prone protein imbalances proteostasis and destabilize other conformationally challenged, metastable proteins. During ageing, the collapse of proteostasis leads to the disruption of multiple cellular activities leading to cell dysfunction and organismal failure. The studies proposed here are to understand how diverse stress signals are sensed by individual cells and tissues in the intact metazoan animal and the roles of stress-inducible transcription factors, HSF1 and Daf-16, to integrate stress biology to enhance cytoprotective networks that suppress the deleterious consequences of ageing and disease. We propose three integrated aims: (1) At the level of the organism, to understand how stress response's in the intact metazoan are regulated by specific neurons that sense and transmit environmental and physiological stress signals to control expression of chaperones in somatic cells. We will identify the signaling pathways that transmit the thermosensory signal from the AFD neurons to regulate the cell non-autonomous control of the heat shock response and HSF1 activity in somatic cells, (2) At the cellular level, to characterize the tissue-specific expression of the family of genes encoding molecular chaperones to elucidate the underlying strategy for chaperone networks in response to stress, during development, and ageing. These studies will provide a network-level understanding of the organizational properties of the eukaryotic chaperome, and (3) At the molecular level, to characterize the regulation of HSF1 by stress-inducible acetylation and deacetylation by the NAD-dependent sirtuin, SIRT1, and the role(s) of this post-translational regulatory pathway in metabolic control of cell stress and lifespan.

Public Health Relevance

Chaperone networks and cytoprotective stress responses regulate the stability of the proteome, and consequently the health of the cell, and lifespan of the organism. An understanding of how these networks are organized and regulated has relevance to a multitude of diseases associated with protein misfolding and aggregation. The studies proposed here are to understand how diverse stress signals are sensed by individual cells and tissues in the intact animal and the roles of stress-inducible transcription factors to integrate stress biology to enhance cytoprotective networks that suppress the deleterious consequences of ageing and disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BST-S (90))
Program Officer
Reddy, Michael K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Schools of Arts and Sciences
United States
Zip Code
Ciryam, Prajwal; Kundra, Rishika; Freer, Rosie et al. (2016) A transcriptional signature of Alzheimer's disease is associated with a metastable subproteome at risk for aggregation. Proc Natl Acad Sci U S A 113:4753-8
Labbadia, Johnathan; Morimoto, Richard I (2015) Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction. Mol Cell 59:639-50
Walther, Dirk M; Kasturi, Prasad; Zheng, Min et al. (2015) Widespread Proteome Remodeling and Aggregation in Aging C. elegans. Cell 161:919-32
Teixeira-Castro, Andreia; Jalles, Ana; Esteves, Sofia et al. (2015) Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain 138:3221-37
Nussbaum-Krammer, Carmen I; Neto, Mário F; Brielmann, Renée M et al. (2015) Investigating the spreading and toxicity of prion-like proteins using the metazoan model organism C. elegans. J Vis Exp :52321
Ciryam, Prajwal; Kundra, Rishika; Morimoto, Richard I et al. (2015) Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases. Trends Pharmacol Sci 36:72-7
Labbadia, Johnathan; Morimoto, Richard I (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435-64
Tatum, Marcus C; Ooi, Felicia K; Chikka, Madhusudana Rao et al. (2015) Neuronal serotonin release triggers the heat shock response in C. elegans in the absence of temperature increase. Curr Biol 25:163-174
Kirstein, Janine; Morito, Daisuke; Kakihana, Taichi et al. (2015) Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments. EMBO J 34:2334-49
Nillegoda, Nadinath B; Kirstein, Janine; Szlachcic, Anna et al. (2015) Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature 524:247-51

Showing the most recent 10 out of 75 publications