(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 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.

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.

Heather Brignull et al. (2001) International C. elegans Meeting "NEURONAL SENSITIVITY TO POLYGLUTAMINE-PROTEIN AGGREGATES IN CAENORHABDITIS ELEGANS ."

Richard Morimoto, Heather Brignull

[International C. elegans Meeting, 2001]

A number of human neurodegenerative diseases such as Huntington's, Parkinson's, and ALS, are characterized by protein aggregates and often associated with aging. The biochemical consequence of misfolded or mutant proteins that self-associate to form protein aggregates should, in principle, be independent of cell type. However, the Huntingtin's gene, for example, is expressed widely in the body, yet protein aggregates and cell death are restricted to specific subsets of neuronal cells. The expression of polyglutamine (polyQ or CAG) expansions, as occurs in Huntington's, results in the appearance of size-dependent protein aggregates in yeast, Drosophila, and Caenorhabditis elegans , thus providing alternate model systems for genetic, biochemical, and cell biological investigations. Of these, C. elegans is a particularly interesting model, as subsets of the 302 neurons in the adult hermaphrodite can be differentially targeted to express aggregation-prone proteins. We have already shown that the expression of polyQ-containing proteins in C. elegans body wall muscle cells causes the size-dependent appearance of protein aggregates. The transition to aggregate formation expansions occurs at approximately 40 polyQ repeats. To investigate the sensitivity of neurons to polyQ induced aggregation, we have made constructs containing polyQ-YFP (Q0, 19, 40, and 82) under the control of the pan-neuronal unc-119 promoter for the generation of transgenic animals. Our preliminary data reveals that Q19-YFP expressing animals exhibit a number of deficiencies including an egg laying defect and uncoordinated phenotype. In contrast, animals expressing Q40-YFP yield transgenic animals with low viability while no progeny expressing Q82-YFP were obtained. Future analysis will take advantage of the both forward and reverse genetics to screen for genes involved in the pan-neuronal, polyQ-induced phenotypes. We will also examine the role of neuronal sub-groups such as sensory or dopaminergic neurons, by generating constructs with subset-specific promoters expressing a series of polyQ-YFPs. This will enable us to determine whether neuronal subsets have differential susceptibility to polyQ induced protein aggregation. The use of subset-specific neuronal promoters will also provide a mechanism for investigating whether polyQ-induced phenotypes differ depending on the neuronal sub-group expressing polyQ.

Veena Prahlad et al. (2005) International Worm Meeting "Identification of a bacterial component that induces postembryonic sexual transformation and genomic instability in C. elegans"

Richard Morimoto, Veena Prahlad

[International Worm Meeting, 2005]

Previous work demonstrated a surprising plasticity in the sex determination mechanism of C. elegans: specific bacterial metabolites could cause XX larvae to post-embryonically change sexual fate and develop as males instead of hermaphrodites. This sexual transformation was accompanied by chromosomal instability and an apparent loss of an X chromosome. In these initial experiments conducted using crude bacterial metabolites, sexual transformation occurred only in XX cross-progeny larvae generated by mating males with hermaphrodites; XX self-progeny did not show a significant degree of sexual transformation. We have subsequently identified a component of bacterial metabolite preparations that appears responsible for the sexual transformation and apparent X chromosome loss. This component is bacterial DNA. Purified Op50 DNA not only induces the sexual transformation of XX cross-progeny, but can also cause 3.6% XX self-progeny larvae to post-embryonically change sexual fate and develop as males. Plasmid DNA, and synthetic single stranded oligonucleotides can also induce both XX cross- and self-progeny to undergo sexual transformation. This ability of DNA to induce sexual transformation appears to be, to some extent, sequence specific. Using synthetic oligonucleotides, we show that the presence of specific CpG motifs within the DNA, repetitive sequences and the oligonucleotide backbone all affect the efficiency of sexual transformation: certain sequences cause as many as 6-10% XX self-progeny larvae to undergo sexual transformation, while others are not effective. These findings are reminiscent of the ability of exogenous DNA to induce an immune response in mammals, and numerous other organisms. The mammalian immune response to specific DNA sequences is presumably a defense mechanism against bacteria and other pathogens. We are currently exploring the extent to which the sexual transformation of C. elegans larvae in response to specific exogenous DNA sequences also reflects the innate immune response of C.elegans to bacterial pathogens. Thus, we are in midst of screening mutants in candidate genes to identify the pathways involved in this process, and using RT-PCR to identify whether specific antibacterial genes known to upregulated during theC. elegans immune response are also specifically upregulated upon exposure to exogenous DNA. The observed DNA-induced generation of males is intriguing. Our studies may provide direct evidence for the Red-Queen Hypothesis that suggests that sexual reproduction in nature is advantageous due to its ability to combat the invasion of pathogens.

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

Janine Kirstein et al. (2008) C.elegans Aging, Stress, Pathogenesis, and Heterochrony Meeting "Interrelation Between Compartment Specific Aggregation And Protein Trafficking"

Richard Morimoto, Janine Kirstein

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

Neurodegenerative diseases such as polyglutamine repeat disease, Lewy bodies in Parkinson disease and amyloid fibrils in Alzheimer''s disease share the accumulation and inclusion of protein aggregates as pathologic feature. The aberrant accumulation of aggregated proteins affects vital cellular processes. The proposed underlying mechanisms of the cellular toxicity range from specific protein-protein interactions to the sequestration of essential proteins by aggregation prone proteins such as polyQ. PolyQ expansions disrupt the global balance of the protein quality control (PQC) system in that the aggregation of a single protein species is sufficient to affect the folding state of metastable proteins (Gidalevitz et al., 2006).However, a previous study demonstrated that also the cellular environment plays a critical role for the aggregation. PolyQ aggregation is abolished when its expression is targeted to the ER or the mitochondrion (Rousseau et al., 2004).The restriction of polyQ aggregation to the cytoplasm and nucleus supports the hypothesis that the deleterious effects could be due to compartment specific components interfering with the aggregation of cytotoxic proteins. Therefore, the overall question I want to address is whether polyQ aggregation in the cytoplasm affects the functionality of proteins localized in the organelles.

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.

Susana Garcia et al. (2006) Neuronal Development, Synaptic Function, and Behavior Meeting "The GABAergic Nervous System Negatively Regulates Protein Misfolding In Muscle Cells of C. elegans"

Susana Garcia, Margarida Amaral, Richard Morimoto

[Neuronal Development, Synaptic Function, and Behavior Meeting, 2006]

The appearance of misfolded protein species and aggregates is associated with pathogenesis in the CAG-repeat diseases and represents a common characteristic of many neurodegenerative diseases. To identify modifiers of polyglutamine aggregation, we employed a forward genetic screen of Caenorhabditis elegans expressing expanded polyglutamine proteins in body wall muscle cells. This screen identified unc-30, a neuron-specific transcription factor, that regulates the synthesis of g-aminobutyric acid (GABA). Animals defective in unc-30 or downstream components in GABA synthesis and signaling exhibited enhanced polyglutamine aggregation in body wall muscle cells. Moreover, stimulation with acetylcholine agonists or GABA antagonists, including nicotine or the organochlorine pesticide lindane, also enhanced polyglutamine aggregation. Our data indicates that the imbalance in muscle cell protein homeostasis is due to cholinergic overstimulation and reveals that dysregulation of neurotransmitters, whether by physiologic means or by environmental toxins, influences directly on protein folding quality control in post-synaptic cells.