Morimoto Richard I et al. (2010) Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI "The Proteostasis Challenge: Regulation of Cellular Stress Responses at the Organismal Level by Neuronal Networks"

Chauve Laetitia, Morimoto Richard I, Silva Catarina, Prahlad Veena

[Aging, Metabolism, Stress, Pathogenesis, and Small RNAs, Madison, WI, 2010]

The stability of the proteome is an essential aspect of cellular health during development, aging, and exposure to environmental and physiological stress. This is achieved by the Proteostasis Network (PN) and the cytoprotective Heat Shock Response (HSR) and Unfolded Protein Response (UPR) that function in concert to suppress the accumulation of misfolded and damaged proteins and direct the expression of a highly functional proteome. We have observed that aging in C. elegans is associated with a sharp decline in the function and folding of metastable proteins during early adulthood. This is associated with a decline in the HSR and UPR, during the peak of fecundity. Activation of Hsf1 (or DAF-16) in early development restores youthful proteostasis revealing the potential to re-adapt, if not restore a protective state. These studies provide a basis to understand the role of Hsf1 and other stress sensors that function at a cellular and molecular level. At the organismal level, however, the HSR is regulated by the AFD thermosensory neurons that transmit the stress signal via specific neurohormones and neuropeptides to somatic tissues to regulate HS gene expression in a cell non-autonomous manner. Unexpectedly, in the presence of functional thermosensory neurons, muscle and intestinal cells accumulate toxic misfolded proteins, which is insufficient to activate the HSR. However, when the activity of thermosensory neurons is altered, the cellular response to misfolded proteins is restored and protein aggregation and toxicity is suppressed. Neuronal control of proteostasis is also regulated at yet another level by cholinergic signaling at the neuromuscular junction. Overexcitation results in enhanced misfolding in post-synaptic muscle cells, whereas increased levels of the cholinergic receptor results in the activation of the HSR, elevated levels of chaperones, and suppression of proteostatic imbalance. These results, reveal that the HSR is organized at the systems level of the organism to sense the stress signal through active neuronal activity, and together with the metabolic state, sets the proteostasis network to ensure stability of the proteome and the health of the organism.

(2015) Cold Spring Harb Symp Quant Biol "A Conversation with Richard Morimoto."

[Cold Spring Harb Symp Quant Biol, 2015]

Richard Morimoto et al. (2008) C.elegans Aging, Stress, Pathogenesis, and Heterochrony Meeting "The Stress of Misfolded Proteins: A Systems Approach to Heat Shock and Proteostasis in Disease and Aging"

Veena Prahlad, Richard Morimoto, Cindy Voisine, Susana Garcia, Catarina Silva, Ning Wang, Monica Beam, Elise Kikis, Anat Ben-Zvi, Tali Gidalevitz

[C.elegans Aging, Stress, Pathogenesis, and Heterochrony Meeting, 2008]

The long-term health of the cell is inextricably linked to proteostasis, a complex network of molecular interactions that maintains the health of proteins. An imbalance in proteostasis, whether caused by environmental or physiological stress, ageing, or the chronic expression of disease-associated proteins (mutant SOD1, huntingtin, polyQ, or Abeta) can be restored by genes that control lifespan (Daf-16) and the heat shock response (Hsf-1). How such folding networks and stress responses are integrated at the molecular and cellular level to the organism has not been examined. The response of C. elegans to heat shock requires the AFD thermosensory neurons and animals harboring mutations in AFD function are defective for induction of the heat shock response in other somatic cells. This AFD requirement is highly selective for activation of heat shock genes by cadmium is unaffected in mutant animals. This reveals that transmission of the heat shock signal is cell non-autonomous and requires active neuronal signaling which serves to integrate temperature-dependent behavioral, metabolic, and stress-specific responses. We draw similar conclusions from a forward genetic screen for enhancers of protein misfolding in body wall muscle cells that identified a mutation in unc-30 that regulates GABAergic signaling. Whether caused by mutations in the GABAergic or cholinergic pathways or by small molecule agonists and antagonists, an imbalance in cholinergic signaling enhances misfolding of polyQ and other metastable proteins in post-synaptic body wall muscle cells.

Morimoto RI et al. (2024) Autophagy "Proteostasis in health and disease: a conversation with Professor Rick Morimoto."

Ktistakis NT, Morimoto RI

[Autophagy, 2024]

Professor Richard (Rick) Morimoto is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research at Northwestern University. He has made foundational contributions to our understanding of how cells respond to various stresses, and the role played in those responses by chaperones. Working across a variety of experimental models, from <i>C</i>. <i>elegans</i> to human neuronal cells, he has identified a number of important molecular components that sense and respond to stress, and he has dissected how stress alters cellular and organismal physiology. Together with colleagues, Professor Morimoto has coined the term "proteostasis" to signify the homeostatic control of protein expression and function, and in recent years he has been one of the leaders of a consortium trying to understand proteostasis in healthy and disease states. I took the opportunity to talk with Professor Morimoto about proteostasis in general, the aims of the consortium, and how autophagy is playing an important role in their research effort.

Townsend SR et al. (1994) Worm Breeder's Gazette "C. elegans Molecular Genetics and Long PCR."

Finelli AL, Savage C, Xie T, Padgett RW, Townsend SR

[Worm Breeder's Gazette, 1994]

C. elegans Molecular Genetics and Long PCR Scott R. Townsend, Cathy Savage, Alyce L. Finelli, Ting Xie, and Richard W. Padgett, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08855

Prahlad, Veena et al. (2013) International Worm Meeting "Serotonergic signaling modulates the heat shock response in C. elegans."

Morimoto, Richard, Prahlad, Veena

[International Worm Meeting, 2013]

The mechanisms that allow for stable physiology, despite the temperature sensitivity of metabolic reactions, are poorly understood. Many organisms, like C. elegans possess neurosensory circuits dedicated to seeking out optimal temperatures. In addition cells within the animal possess conserved mechanisms such as the heat shock response (HSR) mediated by the transcription factor HSF-1, to maintain protein homeostasis despite temperature fluctuations. We discovered that in C. elegans, circuits formed by thermosensory AFD neurons that control behavioral responses to temperature change also control the activation of HSF-1 within all cells throughout the organism, linking sensation of temperature fluctuations to the regulation of metabolic homeostasis. Here we present evidence that the thermosensory control of HSF-1 may occur through the modulation of serotonin signaling by the AFD neurons. Specifically, we show that acute heat shock results in a change in serotonin localization, consistent with its release from the NSM neurons, within minutes after temperature increase. This is concomitant with activation of HSF-1 visualized by changes in its nuclear localization. Serotonergic signaling is necessary for HSF-1 activation and the subsequent induction of the protective heat shock proteins (HSPs): loss of tryptophan hydroxylase or the serotonergic receptors (ser-1/ser-4) prevents HSP induction upon heat shock. In animals harboring loss-of-function mutations in the guanylyl cyclase gcy-8/23 genes required for AFD neuronal response to temperature, serotonin is not released from NSM neurons and HSF1 is not activated after heat shock. HSF-1 activation can be rescued in these thermosensory mutants by the delivery of exogenous serotonin. We are currently investigating how the AFD neurons affect serotonin release by the NSM neurons, and how serotonin influences HSF-1 activity. Serotonergic signaling regulates core body temperature and energy metabolism in mammals. We propose that neuronal control of HSF-1 through serotonin signaling is a conserved mechanism that allows multicellular organisms to adapt to their environment by linking their sensory response to temperature fluctuations with their metabolic state.

Booth LN et al. (2015) Mol Cell "Shockingly Early: Chromatin-Mediated Loss of the Heat Shock Response."

Booth LN, Brunet A

[Mol Cell, 2015]

In this issue of Molecular Cell, Labbadia and Morimoto (2015) show that there is a precipitous decline in stress resistance at the onset of reproduction in C.elegans and that this transition is regulated by changes in repressive chromatin marks.

Bott, Laura et al. (2021) International Worm Meeting "A multi-modal biosensor for monitoring proteostasis in stress and aging"

Sala, Ambre, Brielmann, Renee, Bott, Laura, Morimoto, Richard

[International Worm Meeting, 2021]

Stress and aging can compromise cellular proteostasis and lead to the loss of proteome integrity, a hallmark of many degenerative diseases. Efforts to maintain the functional capacity of the proteostasis network hold promise for prolonging organismal health and reducing the burden of disease, however, the underlying basis for the decline are at present unknown. This is in part due to a lack of available methods for observing the consequence of stressful stimuli on proteome integrity in real time. Here we report a new genetically-encoded biosensor that allows quantitative assessment of proteostasis network capacity in living Caenorhabditis elegans. It is based on a metastable version of dihydrofolate reductase and a conditional proteasome-targeting signal, thereby linking conformational state to protein levels, and fused to a fluorescent protein tag for visualization inside cells. The sensor reveals systemic remodeling of the proteostasis network and identifies distinct cellular states in stress, early aging, and C. elegans models of human disease. Our results indicate that this multi-modal biosensor is a convenient tool for in vivo investigations into proteostasis network regulation in health and disease states.

Sala, Ambre et al. (2021) International Worm Meeting "Embryo Integrity Regulates Maternal Proteostasis and Stress Resilience"

Bott, Laura, Morimoto, Richard, Brielmann, Renee, Sala, Ambre

[International Worm Meeting, 2021]

The proteostasis network (PN) comprises the cellular machineries that regulate protein synthesis, folding, and degradation, to promote proteome integrity. Reduced functionality of the PN during aging results in the accumulation of misfolded and aggregated species that are detrimental for cellular health, and is a hallmark of many age-associated diseases. In multicellular organisms, the PN is regulated by transcellular communication to coordinate proteostasis across tissues and organs in response to physiological and environmental stimuli. The reproductive system in particular is a critical tissue for proteostasis regulation, and signals from the germline initiate the decline of somatic proteostasis and cellular stress responses at reproductive maturity in C. elegans. Here we show that stress resilience and proteostasis are also regulated by embryo-to-mother communication in reproductive adults. To identify genes that act directly in the reproductive system to influence somatic proteostasis, we performed a tissue-targeted RNAi screen for germline modifiers of muscle polyglutamine aggregation. We found that inhibiting the formation of the extracellular vitelline layer of the fertilized embryo inside the uterus suppresses aggregation in multiple somatic tissues and improves maternal stress resilience in an HSF-1-dependent manner. Damage to the vitelline layer of the embryo also prevents the collapse of the heat shock response that normally occurs in early adulthood. This embryo-to-mother pathway relies on DAF-16/FOXO activation in vulva tissues to maintain organismal stress resilience, suggesting that the vulva senses the integrity of the fertilized embryo to detect damage and initiate the organismal response. Gene expression analysis of vitelline layer defective animals using RNA sequencing also revealed that genes involved in lipid metabolism are activated, which is accompanied by elevated fat stores, suggesting a link between fat metabolism and proteostasis in these animals. Our findings reveal a previously undescribed transcellular pathway that links the integrity of the developing progeny to somatic proteostasis regulation and lipid metabolism in the parent. This pathway may serve to reassess commitment to reproduction and promote somatic endurance when progeny production is compromised.

Martinelli SD et al. (1995) International C. elegans Meeting "ACEDB"

Durbin RM, Martinelli SD

[International C. elegans Meeting, 1995]

We hope to provide a demonstration of the current state of the ACeDB worm database on Unix workstations, and if possible Apple Macintosh, throughout the poster sessions. This will be based on the new version 4 release of the acedb software (Jean Thierry-Mieg, Richard Durbin and numerous others), which contains many new features for greater efficiency, more flexible printing, and display of new features.