Cooper AF et al. (1971) "Senescence, quiescence, and cryptobiosis."

Van Gundy SD, Cooper AF

[1971]

This review deals with the biological and physiological characteristics of the Nematoda which may be of significance in studies of biological aging. In general, the discussion is confined to soil-inhabiting nematodes, but supporting evidence is drawn from studies of animal parasitic forms and other kinds of organisms.

Cooper AF et al. (1970) Journal of Nematology "Nematode reproduction in environments of fluctuating aeration."

Stolzy LH, Cooper AF, Van Gundy SD

[Journal of Nematology, 1970]

Reproduction of Aphelenchus avenae, reared on Rhizoctonia solani growing on steamed wheat seeds and Caenorhabditis sp., reared on a mixed bacterial culture grown on oatmeal, was significantly reduced at 5% oxygen and inhibited at 4% oxygen and below. Aeration ranging from atmospheric air (21%) to 10% oxygen had no effect on reproduction. Close interval (5 days or less) fluctuations between high and low oxygen concentrations, inhibited population buildup of Hemicycliophora arenaria on tomato in soil, and of A. avenae and Caenorhabditis sp. in vitro. In soil tests with H. arenaria exposed to 12 hr of nitrogen every three days (in air) inhibited the rate of buildup compared to controls maintained in continuous air. With the in vitro studies, as little as 4 hr nitrogen every 3 days (stored in air) significantly influenced the population numbers.

Cooper JF et al. (2018) J Parkinsons Dis "Modeling Parkinson's Disease in C. elegans."

Van Raamsdonk JM, Cooper JF

[J Parkinsons Dis, 2018]

Parkinson's disease (PD) is an adult onset neurodegenerative disease that is characterized by selective degeneration of neurons primarily in the substantia nigra. At present, the pathogenesis of PD is incompletely understood and there are no neuroprotective treatments available. Accurate animal models of PD provide the opportunity to elucidate disease mechanisms and identify therapeutic targets. This review focuses on C. elegans models of PD, including both genetic and toxicant models. This microscopic worm offers several advantages for the study of PD including ease of genetic manipulation, ability to complete experiments rapidly, low cost, and ability to perform large scale screens for disease modifiers. A number of C. elegans models of PD have been generated including transgenic worms that express -synuclein or LRRK2, and worms with deletions in PRKN/pdr-1, PINK1/pink-1, DJ-1/djr-1.1/djr-1.2 and ATP13A2/catp-6. These worms have been shown to exhibit multiple phenotypic deficits including the loss of dopamine neurons, disruption of dopamine-dependent behaviors, increased sensitivity to stress, age-dependent aggregation, and deficits in movement. As a result, these phenotypes can be used as outcome measures to gain insight into disease pathogenesis and to identify disease modifiers. In this way, C. elegans can be used as an experimental tool to elucidate mechanisms involved in PD and to find novel therapeutic targets that can subsequently be validated in other models.

Cooper JF et al. (2022) Curr Biol "Genetics: A cross-kingdom evolutionary handoff."

Cooper JF, Burton NO, Wang X

[Curr Biol, 2022]

In the fight to resist environmental toxins, Caenorhabditis elegans might have co-opted cysteine-synthase-related enzymes that were likely acquired from algae and then integrated them into a hypoxia-signaling pathway to adapt to cyanide.

Cooper AF et al. (1971) Journal of Nematology "Ethanol production and utilization by Aphelenchus avenae and Caenorhabditis sp."

Van Gundy SD, Cooper AF

[Journal of Nematology, 1971]

In microaerobic and anaerobic environments the principle glycolytic end-product of A. avenae and Caenorhabditis sp. was lactic acid during the first 12-16 hr, after which it was ethanol. Upon return to aerobiosis, 11C-labeled ethanol in the medium was utilized by the nematodes; 14CO2 and some 14C-labeled glycogen was detected. Total dry weight loss of nonfeeding nematodes was 25% greater in the absence of alcohol than in the presence of ethanol or n-propanol. Physical movement and respiration increased and reproduction was extended by alcohol in the bathing

Cooper EL (2010) Phys Life Rev "Self/not self, innate immunity, danger, cancer potential."

Cooper EL

[Phys Life Rev, 2010]

Self/not self is an important hypothesis that has guided research in immunology. It is closely connected to adaptive immunity (restricted to vertebrates) and innate immunity (found in vertebrates and invertebrates). Self/not self is now being challenged and investigators are turning to the danger hypothesis to guide and open new areas of research. Emerging information suggests that genes involved in development of cancer are present in Drosophila and C. elegans. Short life span may not preclude the presence of genes that are related to the development of cancer.

White-Cooper H et al. (2010) Philos Trans R Soc Lond B Biol Sci "Evolution and spermatogenesis."

White-Cooper H, Bausek N

[Philos Trans R Soc Lond B Biol Sci, 2010]

Sexual reproduction depends on the production of haploid gametes, and their fusion to form diploid zygotes. Here, we discuss sperm production and function in a molecular and functional evolutionary context, drawing predominantly from studies in model organisms (mice, Drosophila, Caenorhabditis elegans). We consider the mechanisms involved in establishing and maintaining a germline stem cell population in testes, as well as the factors that regulate their contribution to the pool of differentiating cells. These processes involve considerable interaction between the germline and the soma, and we focus on regulatory signalling events in a variety of organisms. The male germline has a unique transcriptional profile, including expression of many testis-specific genes. The evolutionary pressures associated with gene duplication and acquisition of testis function are discussed in the context of genome organization and transcriptional regulation. Post-meiotic differentiation of spermatids involves very dramatic changes in cell shape and acquisition of highly specialized features. We discuss the variety of sperm motility mechanisms and how various reproductive strategies are associated with the diversity of sperm forms found in animals.

Cooper, Jason et al. (2015) International Worm Meeting "Delaying aging is neuroprotective in C. elegans models of Parkinson's disease."

Dues, Dylan, Spielbauer, Katie, Cooper, Jason, Machiela, Emily, Senchuk, Megan, Van Raamsdonk, Jeremy

[International Worm Meeting, 2015]

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the degeneration of dopamine neurons in the substantia nigra and the formation of alpha-synuclein aggregates called Lewy bodies. While aging is the greatest risk factor for the development of PD, the role of aging in the pathogenesis of PD is not known and it is currently uncertain why the symptoms take many decades to develop when the disease-causing mutations can be present from birth. We hypothesize that there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages. If so, then interventions that increase lifespan should be beneficial in the treatment of PD. To test this hypothesis, we used the powerful genetics of C. elegans, as this worm has been used extensively in aging research. We crossed transgenic worm models of PD expressing either human mutant alpha-synuclein (A53T) or LRRK2 (G2019S) with the long-lived insulin-IGF1 receptor mutant, daf-2. The daf-2 mutation increased the lifespan of both PD mutants. The resulting increase in lifespan ameliorated the degeneration of dopamine neurons in both PD strains and rescued deficits in the dopamine-dependent behaviors including basal slowing and ethanol avoidance. Increasing lifespan through daf-2 mutation also delayed aggregation in a worm model of PD expressing alpha-synuclein in the body wall muscle. Examining potential mechanisms by which delaying aging reduced dopamine neuron loss, we found that the daf-2 mutation rescued deficits in resistance to different stresses that were present in the PD mutant worms. Overall, we show that delaying aging through decreasing the activity of the insulin-IGF1 signaling pathway is beneficial in animal models of PD.

Cooper, J. et al. (2019) International Worm Meeting "Fasting greatly increases production of exophers as a neuronal garbage elimination strategy."

Thieringer, H., Wang, G., Cooper, J., Driscoll, M., Guasp, R.

[International Worm Meeting, 2019]

Misfolded proteins and damaged organelles generate a toxic burden for cells that promote age-associated functional decline. We have discovered that C. elegans neurons can distinguish, package, and literally throw out cellular debris for remote degradation. We call such large ~.4um garbage-containing membrane-surrounded extrusions "exophers" and speculate that exopher production complements known intracellular protein and organelle degradation pathways to maintain homeostasis. Key unanswered questions in this "extracellular garbage elimination" process of exopher-genesis include the nature of the cellular conditions that promote high levels of exopher production. We have shown that multiple treatments that increase proteo-stress (including expression of aggregating human disease proteins, autophagy knockdown via RNAi, disruption of hsf-1, and proteasome inhibition can increase the production of exophers from touch neurons. Likewise, conditions that impair mitochondrial quality (mito-upr and mitophagy) can increase the numbers of exophers that include mitochondria). In general, exophers are produced at a low frequency in basal growth conditions, but stresses that impact known exopher cargoes (protein aggregates and dysfunctional mitochondria) can increase exopher production. We have found that varying nutrient conditions can significantly alter the frequency of exopher production. For instance, high peptone agar culture dramatically decreases exophers and different bacterial food sources can perturb adult exopher production patterns. Strikingly, we note that short periods of fasting can more than double exopher rates. The addition of fasting synergizes with other challenges that themselves do not greatly increase exophers, such as high temperatures or osmotic stress, to elicit even greater levels of exopher production. Our observations underscore that the ejection of exophers from neurons may be a relatively general response to stress and implicate animal-wide physiological conditions in the initiation of neuronal trash elimination. We will present data on how other metabolic perturbations impact exopher-genesis and we speculate on signaling pathways that might mediate whole animal neuroprotective exopher production.

Cooper AA et al. (2006) Science "Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models."

Xu K, Rochet JC, Bhullar B, Cashikar A, Liu K, Cooper AA, Caldwell KA, Hill KJ, Liu F, Gitler AD, Lindquist S, Labaer J, Caldwell GA, Haynes CM, Kolodner RD, Marsischky G, Bonini NM, Cao S, Strathearn KE

[Science, 2006]

Alpha-synuclein (alphaSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson''s disease (PD). In yeast cells and in neurons alphaSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alphaSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic alphaSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alphaSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.