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1.
Sci Rep ; 10(1): 20023, 2020 11 18.
Article in English | MEDLINE | ID: mdl-33208773

ABSTRACT

Glial cells are early sensors of neuronal injury and can store lipids in lipid droplets under oxidative stress conditions. Here, we investigated the functions of the RNA-binding protein, SPEN/SHARP, in the context of Parkinson's disease (PD). Using a data-mining approach, we found that SPEN/SHARP is one of many astrocyte-expressed genes that are significantly differentially expressed in the substantia nigra of PD patients compared with control subjects. Interestingly, the differentially expressed genes are enriched in lipid metabolism-associated genes. In a Drosophila model of PD, we observed that flies carrying a loss-of-function allele of the ortholog split-ends (spen) or with glial cell-specific, but not neuronal-specific, spen knockdown were more sensitive to paraquat intoxication, indicating a protective role for Spen in glial cells. We also found that Spen is a positive regulator of Notch signaling in adult Drosophila glial cells. Moreover, Spen was required to limit abnormal accumulation of lipid droplets in glial cells in a manner independent of its regulation of Notch signaling. Taken together, our results demonstrate that Spen regulates lipid metabolism and storage in glial cells and contributes to glial cell-mediated neuroprotection.


Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Gene Expression Regulation, Developmental , Homeodomain Proteins/metabolism , Lipid Droplets/chemistry , Neuroglia/cytology , Paraquat/toxicity , Parkinson Disease/prevention & control , RNA-Binding Proteins/metabolism , Animals , Drosophila Proteins/genetics , Drosophila melanogaster/drug effects , Drosophila melanogaster/metabolism , Herbicides/toxicity , Homeodomain Proteins/genetics , Male , Neuroglia/drug effects , Neuroglia/metabolism , Parkinson Disease/etiology , Parkinson Disease/metabolism , Parkinson Disease/pathology , RNA-Binding Proteins/genetics
2.
Fly (Austin) ; 9(1): 1-6, 2015.
Article in English | MEDLINE | ID: mdl-26267447

ABSTRACT

We developed a Drosophila model in which the dengue virus NS3 protein is expressed in a tissue specific and inducible manner. Dengue virus NS3 is a multifunctional protein playing a major role during viral replication. Both protease and helicase domains of NS3 are interacting with human and insect host proteins including innate immune components of the host machinery. We characterized the NS3 transgenic flies showing that NS3 expression did not affect fly development. To further study the links between NS3 and the innate immune response, we challenge the flies with gram-positive and gram-negative bacteria. Interestingly, the Drosophila transgenic flies expressing NS3 were more susceptible to bacterial infections than control flies. However ubiquitous or immune-specific NS3 expression affected neither the life span nor the response to a non-infectious stress of the flies. In conclusion, we generated a new in vivo system to study the functional impact of DENV NS3 protein on the innate immune response.


Subject(s)
Drosophila melanogaster/immunology , Immunity, Innate , Viral Nonstructural Proteins/physiology , Animals , Animals, Genetically Modified , Disease Susceptibility , Female , Longevity , Male , Phenotype , Pseudomonas aeruginosa , RNA Helicases/physiology , Serine Endopeptidases/physiology , Staphylococcus aureus , Stress, Physiological
3.
Dev Biol ; 402(2): 208-15, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-25872184

ABSTRACT

Apoptosis is required during development to eliminate superfluous cells and sculpt tissues; spatial and timed control of apoptosis ensures that the necessary number of cells is eliminated at a precise time in a given tissue. The elimination of supernumerary pigment or inter-ommatidial cells (IOCs) depends on cell-cell communication and is necessary for the formation of the honeycomb-like structure of the Drosophila eye. However, the mechanisms occurring during pupal development and controlling apoptosis of superfluous IOC in space and time remain unclear. Here, we found that split-ends (spen) is required for IOC survival at the time of removal of superfluous IOCs. Loss of spen function leads to abnormal removal of IOCs by apoptosis. We show that spen is required non-autonomously in cone cells for the survival of IOCs by positively regulating the Spitz/EGFR pathway. We propose that Spen is an important survival factor that ensures spatial control of the apoptotic wave that is necessary for the correct patterning and formation of the Drosophila eye.


Subject(s)
Apoptosis/physiology , Drosophila Proteins/metabolism , Drosophila/growth & development , Homeodomain Proteins/metabolism , Nuclear Proteins/metabolism , Photoreceptor Cells, Invertebrate/physiology , Retinal Pigment Epithelium/physiology , Signal Transduction/physiology , Animals , Cell Count , Drosophila/metabolism , Fluorescence , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Photoreceptor Cells, Invertebrate/metabolism , Photoreceptor Cells, Invertebrate/ultrastructure , Pupa/metabolism , RNA-Binding Proteins , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/ultrastructure , Statistics, Nonparametric
4.
Fly (Austin) ; 7(4): 213-5, 2013.
Article in English | MEDLINE | ID: mdl-23892363

ABSTRACT

Hedgehog (Hh) is a signaling ligand conserved from flies to humans that is covalently bound to both palmitate and cholesterol moieties. These lipid modifications are crucial for Hh signaling. A recent article reports that in both flies and human-cultured cells a cholesterol-free form of Hh (SHh-N*/Hh-N*) is produced and secreted. In the Drosophila wing disc, Hh associated with Lipoproteins-lipophorin complexes (Lpp) would lead to the accumulation of Cubitus interruptus (Ci), the transcription factor in the Hh pathway but this would be insufficient to activate Hh target genes. On the other hand, Lpp-free Hh-N* would act in synergy with Lpp-associated Hh to eventually activate target gene expression. This suggests that Hh can be secreted in 2 different forms that would have distinct and synergic functions.


Subject(s)
Cholesterol/metabolism , Drosophila Proteins/physiology , Drosophila/metabolism , Hedgehog Proteins/physiology , Models, Biological , Wings, Animal/metabolism , Animals , Drosophila/genetics , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Gene Expression Regulation , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Signal Transduction
5.
J Cell Biol ; 196(2): 233-46, 2012 Jan 23.
Article in English | MEDLINE | ID: mdl-22249291

ABSTRACT

Accurate DNA replication requires proper regulation of replication licensing, which entails loading MCM-2-7 onto replication origins. In this paper, we provide the first comprehensive view of replication licensing in vivo, using video microscopy of Caenorhabditis elegans embryos. As expected, MCM-2-7 loading in late M phase depended on the prereplicative complex (pre-RC) proteins: origin recognition complex (ORC), CDC-6, and CDT-1. However, many features we observed have not been described before: GFP-ORC-1 bound chromatin independently of ORC-2-5, and CDC-6 bound chromatin independently of ORC, whereas CDT-1 and MCM-2-7 DNA binding was interdependent. MCM-3 chromatin loading was irreversible, but CDC-6 and ORC turned over rapidly, consistent with ORC/CDC-6 loading multiple MCM-2-7 complexes. MCM-2-7 chromatin loading further reduced ORC and CDC-6 DNA binding. This dynamic behavior creates a feedback loop allowing ORC/CDC-6 to repeatedly load MCM-2-7 and distribute licensed origins along chromosomal DNA. During S phase, ORC and CDC-6 were excluded from nuclei, and DNA was overreplicated in export-defective cells. Thus, nucleocytoplasmic compartmentalization of licensing factors ensures that DNA replication occurs only once.


Subject(s)
Caenorhabditis elegans/embryology , Caenorhabditis elegans/genetics , DNA Replication , Embryo, Nonmammalian/metabolism , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Division , Chromatin/metabolism , DNA/metabolism , Ligases/metabolism , Origin Recognition Complex/metabolism , Time-Lapse Imaging
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