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[
Exp Gerontol,
2006]
Caenorhabditis elegans has been used to model aspects of a number of age-associated neurodegenerative diseases, including Alzheimer''s, Parkinson''s and Huntington''s diseases. These models have typically involved the transgenic expression of disease-associated human proteins. Here I describe my laboratory''s specific experience engineering C. elegans models of Alzheimer''s disease, and give a general consideration of the advantages and disadvantages of these C. elegans models. The type of insights that might be gained from using these (relatively) simple models are highlighted. In particular, I consider the potential these models have for uncovering common and unique fundamental toxic mechanisms underlying human neurodegenerative diseases.
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[
Hermann, Editeurs des Sciences et des Arts. Paris, France.,
2002]
L'espce Caenorhabditis elegans fut dcrite en 1900 Alger par E. Maupas, qui s'intressait son mode de reproduction hermaphrodite. Plus tard, vers le milieu du vingtime sicle, V. Nigon et ses collaboratuers Lyon tudirent les reorganizations cellulaires accompagnant la fecundation et les premiers clivages. J. Brun isola les preiers mutants morpholgiques.
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[
Curr Biol,
2001]
When meiotic cells complete S phase, homologous chromosomes pair, synapse and undergo recombination. A checkpoint protein is somehow required for meiotic chromosome pairing in C. elegans, thus providing a direct link between S phase and the rest of the meiotic program.
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[
Toxins (Basel),
2016]
Staphylococcus aureus is an opportunistic pathogen and the leading cause of a wide range of severe clinical infections. The range of diseases reflects the diversity of virulence factors produced by this pathogen. To establish an infection in the host, S. aureus expresses an inclusive set of virulence factors such as toxins, enzymes, adhesins, and other surface proteins that allow the pathogen to survive under extreme conditions and are essential for the bacteria's ability to spread through tissues. Expression and secretion of this array of toxins and enzymes are tightly controlled by a number of regulatory systems. S. aureus is also notorious for its ability to resist the arsenal of currently available antibiotics and dissemination of various multidrug-resistant S. aureus clones limits therapeutic options for a S. aureus infection. Recently, the development of anti-virulence therapeutics that neutralize S. aureus toxins or block the pathways that regulate toxin production has shown potential in thwarting the bacteria's acquisition of antibiotic resistance. In this review, we provide insights into the regulation of S. aureus toxin production and potential anti-virulence strategies that target S. aureus toxins.
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[
Nat Rev Mol Cell Biol,
2014]
Many organs contain networks of epithelial tubes that transport gases or fluids. A lumen can be generated by tissue that enwraps a pre-existing extracellular space or it can arise de novo either between cells or within a single cell in a position where there was no space previously. Apparently distinct mechanisms of de novo lumen formation observed in vitro - in three-dimensional cultures of endothelial and Madin-Darby canine kidney (MDCK) cells - and in vivo - in zebrafish vasculature, Caenorhabditis elegans excretory cells and the Drosophila melanogaster trachea - in fact share many common features. In all systems, lumen formation involves the structured expansion of the apical plasma membrane through general mechanisms of vesicle transport and of microtubule and actin cytoskeleton regulation.
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[
Biochem Soc Trans,
2020]
DNA replication is a complex process that needs to be executed accurately before cell division in order to maintain genome integrity. DNA replication is divided into three main stages: initiation, elongation and termination. One of the key events during initiation is the assembly of the replicative helicase at origins of replication, and this mechanism has been very well described over the last decades. In the last six years however, researchers have also focused on deciphering the molecular mechanisms underlying the disassembly of the replicative helicase during termination. Similar to replisome assembly, the mechanism of replisome disassembly is strictly regulated and well conserved throughout evolution, although its complexity increases in higher eukaryotes. While budding yeast rely on just one pathway for replisome disassembly in S phase, higher eukaryotes evolved an additional mitotic pathway over and above the default S phase specific pathway. Moreover, replisome disassembly has been recently found to be a key event prior to the repair of certain DNA lesions, such as under-replicated DNA in mitosis and inter-strand cross-links (ICLs) in S phase. Although replisome disassembly in human cells has not been characterised yet, they possess all of the factors involved in these pathways in model organisms, and de-regulation of many of them are known to contribute to tumorigenesis and other pathological conditions.
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[
WormBook,
2007]
Because of their free-living life cycle alternatives, Strongyloides and related nematode parasites may represent the best models for translating C. elegans science to the study of nematode parasitism. S. stercoralis, a significant pathogen of humans, can be maintained in laboratory dogs and gerbils. Biosafety precautions necessary for work with S. stercoralis, though unfamiliar to many C. elegans researchers, are straightforward and easily accomplished. Although specialized methods are necessary for large-scale culture of the free-living stages of S. stercoralis, small-scale cultures for experimental purposes may be undertaken using minor modifications of standard C. elegans methods. Similarly, the morphological similarities between C. elegans and the free-living stages of S. stercoralis allow investigational methods such as laser cell ablation and DNA transformation by gonadal microinjection to be easily adapted from C. elegans to S. stercoralis. Comparative studies employing these methods have yielded new insights into the neuronal control of the infective process in parasites and its similarity to regulation of dauer development in C. elegans. Furthermore, we have developed a practical method for transient transformation of S. stercoralis with vector constructs having various tissue- and cell-specific expression patterns and have assembled these into a modular vector kit for distribution to the community.
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[
Ann Pharm Fr,
2006]
The Nematode Caenorhabditis elegans (C. elegans) is an established model increasingly used for studying human disease pathogenesis. C. elegans models are based on the mutagenesis of human disease genes conserved in this Nematode or on the transgenesis with disease genes not conserved in C. elegans. Genetic examinations will give new insights on the cellular and molecular mechanisms that are altered in some neurodegenerative diseases like Duchenne''s muscular dystrophy, Huntington''s disease and Alzheimer''s disease. C. elegans may be used for primary screening of new compounds that may be used as drugs in these diseases.
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Qi Y, Cui J, Wang R, Tang C, Shan K, Feng N, Cui G, Chen YQ, Qu H, Fu G, Li J
[
Eur J Med Chem,
2021]
Fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, is an attractive therapeutic target for diseases characterized by excessive lipid accumulation. Many FASN inhibitors have failed in the clinical trial phase, largely because of poor solubility and safety. In this study, we generated a novel small-molecule FASN inhibitor by structure-based virtual screening. PFI09, the lead compound, is easy to synthesize, and inhibits the lipid synthesis in OP9 mammalian cell line and Caenorhabditis elegans as well as the proliferation of several cancer cell lines via the blockade of FASN. Mechanistic investigations show that PFI09 induces S-phase arrest, cell division reduction and apoptosis. We also develop a chemically stable analog of PFI09, MFI03, which reduces the proliferation of PC3 tumor cells both invitro and invivo, without toxicity to mice. In summary, our data suggest that MFI03 is an effective FASN inhibitor and a promising antineoplastic drug candidate.
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[
Journal of Cell Science,
2004]
How do cells regulate centrosome number? A canonical duplication cycle generates two centrosomes from one in most proliferating cells. Centrioles are key to this process, and molecules such as centrins, SAS-4 and ZYG-1 govern daughter centriole formation. Cdk2 activity probably couples centrosome duplication with the S phase, and a licensing mechanism appears to limit centrosome duplication to once per cell cycle. However, such mechanisms must be altered in some cells - for example, spermatocytes - in which centrosome duplication and DNA replication are uncoupled. There are also alternative pathways of centrosome biogenesis. For example, one centrosome is reconstituted from two gametes at fertilization; in this case, the most common strategy involves differential contributions of centrioles and pericentriolar material (PCM) from each gamete. Furthermore, centrioles can sometimes form de novo from no apparent template. This occurs, for instance, in the early mouse embryo and in parthenogenetic species and might rely on a pre-existing seed that resides within PCM but is not visible by