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Curr Top Microbiol Immunol,
2012]
Phosphatidylinositol transfer proteins (PITPs), comprising five members in the human genome are implicated in the non-vesicular traffic of phosphatidylinositol (PI) between intracellular membranes and the plasma membrane. Three members of the PITP family (PITP, PITP, and RdgB (retinal degeneration type B) alt. name PITPNC1) are present as single domain proteins and two (RdgBI and RdgBII alt. name PITPNM1 and PITPNM2) are present as multi-domain proteins with the PITP domain located at the N-terminus. The hallmark of PITP proteins is to extract PI molecules from a membrane, sequester in its binding pocket and deposit the lipid to membranes. PITPs regulate the synthesis of phosphoinositides (PPIs) either by delivery of the substrate, PI to specific membrane compartments or by potentiating the activities of the lipid kinases, or both. In the light of recent studies, we propose that PITPs are regulators of phosphoinositide pathways by recruitment to membranes through specific protein interactions to promote molecular exchange between closely opposed membranes i.e., at membrane contact sites. Individual PITP proteins play highly specific roles in many biological processes including neurite outgrowth, membrane traffic, cytokinesis, and sensory transduction in mammals as well as in the model organisms, Drosophila, Caenorhabditis elegans, and zebrafish. The common requirement for the diverse functions for all PITPs is their ability to bind PI and coupling its function to phosphoinositide-dependent pathways.
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Semin Cell Dev Biol,
2001]
Phosphatidylinositol transfer proteins (PITPs) are lipid binding proteins that can catalyse the transfer of phosphatidylinositol (PI) from membranes enriched in PI to PI-deficient membranes. Three soluble forms of PITP of 35--38 kDa (PITP alpha, PITP beta and rdgB beta) and two larger integral proteins of 160 kDa (rdgB alpha I and II), which contain a PITP domain, are found in mammalian cells. PITPs are intimately associated with the compartmentalised synthesis of different phosphorylated inositol lipids. PI is the primary inositol lipid that is synthesised at the endoplasmic reticulum and is further phosphorylated in distinct membrane compartments by many specific lipid kinases to generate seven phosphorylated inositol lipids which are required for both signalling and for membrane traffic. PITPs play essential roles in both signalling via phospholipase C and phosphoinositide 3-kinases and in multiple aspects of membrane traffic including regulated exocytosis and vesicle biogenesis.
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Biochem Soc Trans,
2016]
Phosphatidylinositol (PI) is the precursor lipid for the synthesis of PI 4,5-bisphosphate [PI(4,5)P2] at the plasma membrane (PM) and is sequentially phosphorylated by the lipid kinases, PI 4-kinase and phosphatidylinositol 4-phosphate (PI4P)-5-kinase. Receptor-mediated hydrolysis of PI(4,5)P2 takes place at the PM but PI resynthesis occurs at the endoplasmic reticulum (ER). Thus PI(4,5)P2 resynthesis requires the reciprocal transport of two key intermediates, phosphatidic acid (PA) and PI between the ER and the PM. PI transfer proteins (PITPs), defined by the presence of the PITP domain, can facilitate lipid transfer between membranes; the PITP domain comprises a hydrophobic cavity with dual specificity but accommodates a single phospholipid molecule. The class II PITP, retinal degeneration typeB (RdgB) is a multi-domain protein and its PITP domain can bind and transfer PI and PA. In Drosophila photoreceptors, a well-defined G-protein-coupled phospholipase C (PLC) signalling pathway, phototransduction defects resulting from loss of RdgB can be rescued by expression of the PITP domain provided it is competent for both PI and PA transfer. We propose that RdgB proteins maintain PI(4,5)P2 homoeostasis after PLC activation by facilitating the reciprocal transport of PA and PI at ER-PM membrane contact sites.
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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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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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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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Mol Cell,
2004]
Applying a combination of innovative approaches to understanding neuronal gene regulation in C. elegans, an article in the latest Developmental Cell (Wenick and Hobert, 2004) gives hope that reading the genome''s transcriptional regulatory code may one day be possible.
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Front Biosci,
2004]
Alzheimer''s disease (AD) is affecting more people every year due to the increase in elderly population. This disease is characterized by senior plaques, containing aggregated amyloid beta peptide (A beta), and neurofibrillary tangles in the AD brains. The A beta depositions are thought to increase in cellular oxidative stress, which subsequently produces neuronal cell death in the patient s brain, causing loss of memory and, in the latter stages, dementia. Diverse models have been established to test this, "Amyloid Toxicity Hypothesis of AD". Among these, the use of the nematode Caenorhabditis elegans has some advantages. This invertebrate has its entire genome known, as well as numerous gene homologues to those seen in humans. In relationship with the cell model, the nematode gives the benefit of an organismal view of the disease. The nematode''s short life span proves useful, when compared with that of mice, allowing mechanistic studies of the disease and pharmacological treatments. Alongside with other laboratories, we have used this in vivo model to correlate the Abeta expression with its toxicity through the observance of the organism''s behavior to provide a better understanding of the cellular processes underlining AD.