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[
J Cell Biol,
2024]
Racecar drivers use left-foot braking, i.e., simultaneously engaging brake and throttle, to carefully balance acceleration and traction when navigating chicanes. In this issue, Lara-Gonzalez et al. (https://doi.org/10.1083/jcb.202308034) show that C. elegans embryos employ the molecular equivalent of left-foot braking to faithfully speed through mitosis.
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Fritsche RF, Boland S, Zagoriy V, Czerwonka R, Reimann J, Schmidt U, Sampaio JL, Knolker HJ, Kurzchalia TV, Penkov S, Lubken T
[
Nat Chem Biol,
2017]
The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is indispensable. Here, we present a novel class of C. elegans phosphorylated glycosphingolipids, phosphoethanolamine glucosylceramides (PEGCs), capable of rescuing larval arrest induced by sterol starvation. We describe the total synthesis of a major PEGC species and demonstrate that the PEGC synthetic counterpart suppresses the dauer-constitutive phenotype of Niemann-Pick C1 (NPC1) and DAF-7/TGF- mutant worms caused by impaired intracellular sterol trafficking. PEGC biosynthesis depends on functional NPC1 and TGF-, indicating that these proteins control larval development at least partly through PEGC. Furthermore, glucosylceramide deficiency dramatically reduced PEGC amounts. However, the resulting developmental arrest could be rescued by oversaturation of food with cholesterol. Taken together, these data show that PEGC is essential for C. elegans development through its regulation of sterol mobilization.
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Lubken, Tilo, Boland, Sebastian, Zagoriy, Vyacheslav, Fritsche, Raphael, Penkov, Sider, Knolker, Hans-Joachim, Czerwonka, Regina, Schmidt, Ulrike, Reimann, Jakob, Sampaio, Julio, L., Kurzchalia, Teymuras, V.
[
International Worm Meeting,
2017]
Caenorhabditis elegans (C. elegans) cannot synthesize cholesterol de novo, and requires exogenous cholesterol to progress through its four larval stages. Previously, we showed that worms grown for 2 generations in the absence of cholesterol arrest early in development. This suggests that maternal contributions of sterols are exploitable only in the first generation, but sterol reservoirs are either depleted or inaccessible by the second generation. Here, we present a novel class of phosphorylated glycosphingolipids, which we coined phosphoethanolamine glucosylceramides (PEGCs), that can overcome the sterol deprivation-induced larval arrest. However, they are not direct substitutes for cholesterol because they rescue larval arrest in only one additional generation. Instead, we propose a new model where larval arrest in the second generation of continious sterol deprivation is due not to depletion of internal reservoirs, but a failure to mobilize those reservoirs for promoting growth/development through PEGCs-induced mobilization of internal sterol pools. More precisely, we found that NPC1 and DAF-7 mutants, which display a Daf-c phenotype due to an impaired sterol transport to places of DA synthesis, are rescued by feeding PEGC. Moreover, the biosynthesis of PEGC depends on functional NPC1 and TGF- beta , indicating that these proteins control larval development at least partly through promoting increases in PEGC. Furthermore, glucosylceramide deficiency dramatically reduced PEGC amounts; however, the resulting developmental arrest could be rescued by over-saturation of food with cholesterol. This indicates that PEGC is a major regulator of cholesterol utilization in C. elegans and, thus, of development. The remarkable similarity in sterol trafficking between C. elegans and other metazoans, including mammals, suggests PEGCs might be conserved regulators of sterol transport.
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[
Nat Struct Mol Biol,
2017]
Separase is a caspase-family protease that initiates chromatid segregation by cleaving the kleisin subunits (Scc1 and Rec8) of cohesin, and regulates centrosome duplication and mitotic spindle function through cleavage of kendrin and Slk19. To understand the mechanisms of securin regulation of separase, we used single-particle cryo-electron microscopy (cryo-EM) to determine a near-atomic-resolution structure of the Caenorhabditis elegans separase-securin complex. Separase adopts a triangular-shaped bilobal architecture comprising an N-terminal tetratricopeptide repeat (TPR)-like -solenoid domain docked onto the conserved C-terminal protease domain. Securin engages separase in an extended antiparallel conformation, interacting with both lobes. It inhibits separase by interacting with the catalytic site through a pseudosubstrate mechanism, thus revealing that in the inhibited separase-securin complex, the catalytic site adopts a conformation compatible with substrate binding. Securin is protected from cleavage because an aliphatic side chain at the P1 position represses protease activity by disrupting the organization of catalytic site residues.
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Pennington PR, Quartey MO, Nyarko JNK, Parsons MP, Maley JM, Heistad RM, Leary SC, Barnes JR, Knudsen KJ, De Carvalho CE, Bolanos MAC, Buttigieg J, Mousseau DD
[
Sci Rep,
2021]
The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).
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[
Worm Breeder's Gazette,
2003]
Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.
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[
International Journal of Developmental Biology,
1998]
Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.
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[
Front Pharmacol,
2020]
Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.
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[
Curr Biol,
2011]
Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.
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[
Naturwissenschaften,
2004]
Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.