Monica Driscoll (2008) C.elegans Neuronal Development Meeting "Neuronal Degeneration, Aging and Regeneration in C. elegans"

Monica Driscoll

[C.elegans Neuronal Development Meeting, 2008]

The amazing cellular characterization of the C. elegansnervous system (thanks, John White and colleagues!), coupled with the power of molecular and genetic manipulations that can be applied in this transparent nematode, render the worm a highly appealing model for the investigation of conserved mechanisms of neuronal degeneration, aging and regeneration. Like in mammals, C. elegans necrotic death can be initiated by hyper-activated ion channels of two types: DEG/ENaCs, and glutamate-gated channels. Death-inducing mutations hyperactivate the Ca/Na-permeable MEC-4(D) DEG/ENaC channel, which induces catastrophic ER calcium release and activates proteases to induce necrotic death. MEC-4-related Ca-permeable DEG/ENaC ASIC1a is hyperactivated in ischemia to induce neuronal loss in mouse brain. Also in mammalian stroke, neuronal over-stimulation by glutamate (Glu) hyperactivates post-synaptic Glu receptor ion channels (GluRs) and triggers excitotoxic neurodegeneration. Malfunction of surface glutamate transporters (sGluTs), which normally remove Glu from the synapse, elevates local synaptic glutamate concentration to induce excitotoxicty. We have found that deletion of sGluT glt-3 acts synergistically with activated Gas* signaling to promote extensive necrosis, acting through GluRs of the AMPA subtype and Type 9 calcineurin-modulatedadenylyl cyclase acy-1. Our hope is that genetic and pharmacological analyses of C. elegans necrosis will provide insight applicable into preventing neuronal loss in the clinic. Our interest in neurodegeneration provoked a natural curiosity about the aging of the C. elegans nervous system and potential contributions of neuronal degeneration to aging. Our studies revealed that neuronal death per se does not drive the aging of the animal. Rather, more subtle changes in the nervous system apply. Stochastic factors seem to exert a major impact on the aging of the animal and the nervous system. After years of research focus on death and deterioration, we sought to add in a more positive topic of study. We are collaborating with Aravi Samuel''s lab to address the role of cell death machinery in the process of neuronal regeneration consequent to laseraxotomy (see abstracts by Pinan-Lucarre, Gabel, et. al.; Gabel et al.). These studies have revealed a role for CED-3 caspase as well as ER calcium-storing chaperone calreticulin in a cell-autonomous mechanism of neuronal regeneration, suggesting that the bad boys of apoptosis and necrosis can make good.

Dhillon HS et al. (1994) Worm Breeder's Gazette "More Degenerins in the Worm?"

Dhillon HS, Driscoll MA

[Worm Breeder's Gazette, 1994]

More degenerins in the worm? Harbinder Singh Dhillon and Monica Driscoll. Department of Molecular Biology and Biochemistry, Rutgers University, Center for Advanced Biotechnology and Medicine, 679 Hoes lane, Piscataway, N.J. 08855

Hall DH et al. (1994) Worm Breeder's Gazette "Cytology of Degenerin-Induced Cell Death in the PVM Neuron"

Driscoll MA, Chalfie M, Gu GQ, Hall DH, Gong L

[Worm Breeder's Gazette, 1994]

Cytology of degenerin-induced cell death in the PVM neuron David H. Hall, Guoqiang Gu+, Lei Gong#, Monica Driscoll#, and Martin Chalfie+, * Dept. Neuroscience, Albert Einstein College of Medicine, Bronx, N.Y. 10461 + Dept. Biological Sciences, Columbia University, New York, N.Y. 10027 # Dept. Molecular Biology and Biochemistry, Rutgers University, Piscataway, N.J. 08855

Driscoll MA et al. (1992) Worm Breeder's Gazette "A Hot-Spot for Mutations in a Cys-rich Domain of mec-4 Includes a Site Which,When Mutated, Can Suppress a Dominant Death-Inducing Mutation in Cis"

Driscoll MA, Hong K

[Worm Breeder's Gazette, 1992]

A Hot-spot for Mutations in a Cys-rich Domain of mec-4 Includes a Site Which, When Mutated, Can Suppregg a Dominant Death inducing Mutation in Cis Kyonsoo Hong and Monica Driscoll. Department of Molecular Biology and Biochemistry, Rutgers University, Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, N.J. 08855 (908) 463-5193

Liebau, Andrew et al. (2015) International Worm Meeting "Screen for Micro-RNA Activation of the Dietary Restriction Pathway and for Effect of Micro-RNA Deletions on Fitness in Caenorhabditis elegans."

Liebau, Andrew, Vora, Mehul, Driscoll, Monica

[International Worm Meeting, 2015]

Caloric /Dietary Restriction (CR/DR) is a highly conserved survival response that that extends both lifespan and healthspan in organisms experiencing lowered caloric intake with good nutrition. The Driscoll Lab has previously shown that C. elegans micro RNA-80 (mir-80) represses the dietary restriction pathway in well-fed organisms. The mir-80 mutant constitutively undergoes dietary restriction in spite of food availability and receives the benefit of a longer and healthier life. We are currently studying the mir-80 family of micro RNAs for their role in DR regulation. Current data suggests that one family member is critical for the DR state when mir-80 is deleted. We are also searching for miRNAs that have the opposite function of mir80, ones that are required for the animal to undergo DR. Preliminary results using markers characteristic of DR have identified several candidate miRNAs that appear to have a role in the regulation of DR. Mutants in these genes appear to be unable to undergo DR when they are starved.Another avenue of research we are undertaking is the investigation of the effect that miRNA deletions have on the healthspan of C. elegans in general. The computer program CeleST, developed by the Driscoll lab to analyze the swimming of nematodes, has identified several miRNA mutations that affect muscle health. We are currently testing these for additional longevity phenotypes.

Onken, Brian et al. (2013) International Worm Meeting "Perturbations of Glycolytic Flux Differentially Impact Healthspan via the Insulin Signaling and Dietary Restriction Pathways."

Driscoll, Monica, Onken, Brian

[International Worm Meeting, 2013]

In Caenorhabditis elegans, adding excess glucose to the growth medium shortens lifespan [1, 2, 3], while inhibiting the glycolytic enzyme hexokinase with the glucose analog 2-deoxyglucose increases lifespan [1]. We have shown that disrupting genes encoding two other glycolytic enzymes that catalyze unidirectional, irreversible reactions in glycolysis lengthens C. elegans median lifespan, induces large gains in youthful locomotory ability, and triggers a fluorescent biomarker that distinguishes a healthy metabolic state. Conversely, disrupting counterpart unidirectional gluconeogenic genes decreases nematode healthspan. In investigating potential longevity-related pathways that might impinge upon glucose metabolism, we found that disrupting glycolytic genes increases healthspan through the FOXO transcription factor DAF-16, which is also required for the increased lifespan seen with lowered levels of insulin signaling, and which is downregulated by increased glucose availability [2]. Strikingly, we also found that gluconeogenic activity is specifically required for increased healthspan under dietary restriction, and that the SKN-1 transcription factor, which is required for the beneficial effects of dietary restriction [4], is also needed for the healthspan effects seen with decreased gluconeogenesis. In addition, we found that a transcriptional reporter for gluconeogenic gene pck-2 is induced by several dietary restriction regimens in a SKN-1-dependent manner. These results provide evidence for an intriguing new paradigm: breakdown of glucose via glycolysis negatively impacts healthy aging through insulin signaling and DAF-16, while dietary restriction engages the reciprocal gluconeogenic pathway to promote healthspan via SKN-1. Our observations support that healthspan might be optimized via dietary, pharmacological, or genetic interventions that increase gluconeogenic activity or decrease glycolysis. 1. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, et al. (2007). Cell Metab 6: 280-293. 2. Lee SJ, Murphy CT, Kenyon C (2009). Cell Metab 10: 379-391. 3. Schlotterer A, et al. (2009). Diabetes 58: 2450-2456. 4. Bishop NA, Guarente L (2007). Nature 447: 545-549.

Chuang, Edward et al. (2021) International Worm Meeting "Material states of protein cargo in neuronal exophers"

Driscoll, Monica, Chuang, Edward

[International Worm Meeting, 2021]

Neurodegenerative diseases are devastating disorders that affect millions of Americans and cause hundreds of thousands of deaths each year. Amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gherig's disease, is caused by the degeneration of upper and lower motor neurons that results in progressive paralysis, whereby cognitively healthy patients are "trapped" within paralyzed bodies and experience respiratory failure and death within 3-5 years. Protein aggregation is a hallmark of pathology in neurodegenerative diseases. FUS and TDP43 are two RNA-binding proteins that are commonly found to aggregate in the neurons of patients with ALS. Aggregation pathology spreads through the brain along neuronal circuits suggesting a mechanism of neuronal transfer of aggregates that may be exploited for novel interventions against these devastating neurodegenerative diseases. Our lab has recently observed that C. elegans neurons can expel aggregated mCherry or PolyQ protein from the soma in large membrane-bound vesicles (called exophers) to promote proteostasis within the neuron. It is interesting that proteins such as FUS and TDP43 can form a variety of material states including liquid droplets, hydrogels, and insoluble aggregates. The material state phenomenon is also observed for the P granule proteins PGL-3, which forms a liquid, and MEG-3, which forms a hydrogel. It is unknown whether liquid droplets or hydrogels (or both or neither) are expelled in exophers. We are expressing FUS, TDP43, PGL-3, and MEG-3 in C. elegans touch neurons to determine their capacity to be recruited to exophers. The results I will present will further our understanding of exopher cargo selection and the potential for exopher biology to be a target for intervening in neurodegenerative diseases.

Onken, Brian et al. (2015) International Worm Meeting "Dietary restriction promotes healthspan via a glucagon-like signaling pathway in C. elegans."

Driscoll, Monica, Onken, Brian

[International Worm Meeting, 2015]

A major goal of aging research is to understand the underlying relationship between nutritional intake, metabolism, and healthy aging. Low-glycemic index diets have been shown to reduce risk of age-related metabolic diseases such as diabetes and cardiovascular disease, and reduced caloric intake via dietary restriction (DR) increases healthspan across species. One potential approach for supporting healthy aging is via interventions that engage healthspan-promoting metabolism.Our previous work has shown that interventions that block glycolysis result in striking healthspan gains, while increased gluconeogenic activity can similarly promote healthy aging. We have also shown that DR increases healthspan in a manner that requires gluconeogenic gene expression. These results suggest that molecular pathways that engage gluconeogenic metabolism and inhibit glycolysis may generally work to improve the quality of aging. In mammals, the glucagon signaling pathway works opposite to the insulin pathway to regulate blood sugar levels: when circulating glucose levels are low, glucagon promotes glucose production in the liver by stimulating glycogenolysis and gluconeogenesis while inhibiting glycogen synthesis and glycolysis. We reason that glucagon signaling, like DR (and unlike insulin signaling), may have an overall positive impact on healthspan. To investigate this, we screened for potential glucagon receptors in Caenorhabditis elegans, and found one candidate, pdfr-1, which is required for the induction of gluconeogenic gene expression under DR and for the long lifespan of dietary-restricted animals. In the mammalian glucagon signaling pathway, the G protein alpha subunit coupled to the glucagon receptor activates adenylate cyclase, which increases cAMP levels to activate protein kinase A, which in turn inhibits glycolytic activity and promotes gluconeogenesis. Similar to pdfr-1, we find that a C. elegans adenylate cyclase ortholog, acy-1, is required for increased lifespan under DR. We also find that disruption of kin-2, which encodes the inhibitory subunit of the C. elegans PKA ortholog kin-1, triggers biomarkers for the DR state and results in dramatic healthspan increases that mirror those seen under DR. Our observations reveal a potential C. elegans glucagon pathway that is required for DR healthspan benefits, and suggest novel approaches to improving the quality of aging via interventions that promote glucagon pathway signaling.

Coleman-Hulbert, Anna L et al. MicroPubl Biol

Sedore, Christine A, Phillips, Patrick C, Coleman-Hulbert, Anna L, Driscoll, Monica, Banse, Stephan A, Lithgow, Gordon J, Guo, Max, Johnson, Erik

[MicroPubl Biol, 2019]

The authors, Coleman-Hulbert, AL; Johnson, E; Sedore, CA; Banse, SA; Guo, M2; Driscoll, M3; Lithgow, GJ; and Phillips, PC, submit the following correction. The first reference in the methods paragraph should be (Lucanic et al., 2017; Plummer et al., 2017) and should not be letteredaccordingly. We assayed lifespan in response to imatinib mesylate exposure in three Caenorhabditis species in triplicate using our previously published workflow (Lucanic et al. 2017a; b). should be corrected to: We assayed lifespan in response to imatinib mesylate exposure in three Caenorhabditis species in triplicate using our previously published workflow (Lucanic et al., 2017; Plummer et al., 2017).

Vora, Mehul et al. (2011) International Worm Meeting "The conserved microRNA miR-80 negatively regulates C. elegans longevity through inhibition of the dietary restriction pathway."

Driscoll, Monica, Vora, Mehul, Shah, Mitalie, Ostafi, Silvana

[International Worm Meeting, 2011]

Dietary restriction-limitation of caloric intake without deleterious reduction in essential nutrients-extends lifespan and reduces the incidence of age-associated disease across species. Identification of regulators of the DR state that might bypass the calorie limitation requirement but nonetheless engage metabolism to promote healthy aging are of considerable interest. We previously identified a unique fluorimetric signature for the C. elegans DR state (Excitation maximum peak shift for naturally fluorescent age pigments and lipofuscin[1]) that is not found in other long-lived mutant strains. We exploited this discovery to screen through the available miRNA deletion mutants to identify mir mutants that might persist in a constitutive DR-like state. We identified a single mir mutant, affecting the conserved mir-80 gene, which robustly exhibits the fluorimetric DR signature and lives longer than wild type. mir-80 mutants also exhibit reduced fecundity and appear pale and thin. Like DR-animals, mir-80(nDf53) is hypersensitive to the DR mimetic drug metformin, which is the drug response expected for animals that are already in DR (pushed over the edge into starvation)[2]. Interestingly, a transcriptional GFP reporter for mir-80 is responsive to food (upregulated in the presence of food and down-regulated in absence of food) and a key molecular reporter of DR, the transcription factor skn-1, is activated by mir-80 deletion. We will present preliminary data on several genes that are needed for mir-80(nDf53)-regulated DR benefits. In conclusion, we will provide evidence that miR-80 negatively regulates genes that are involved in DR metabolism. We report the first instance of a metazoan microRNA that affects longevity through dietary restriction. 1.Gerstbrein, B., et al., In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell, 2005. 4(3): p. 127-137. 2.Onken, B. and M. Driscoll, Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS ONE, 2010. 5(1): p. e8758.