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At least 1,261 records · Page 70Linked to original sources
PubMed2005

Neurodegenerative mutants in Drosophila: a means to identify genes and mechanisms involved in human diseases?

There are 50 ways to leave your lover (Simon 1987) but many more to kill your brain cells. Several neurodegenerative diseases in humans, like Alzheimer's disease, have been intensely studied but the underlying cellular and molecular mechanisms are still unknown for most of them. For those syndromes where associated gene products have been identified their biochemistry and physiological as well as pathogenic function is often still under debate. This is in part due to the inherent limitations of genetic analyses in humans and other mammals and therefore experimentally accessible invertebrate in vivo models, such as Caenorhabditis elegans and Drosophila melanogaster, have recently been introduced to investigate neurodegenerative syndromes. Several laboratories have used transgenic approaches in Drosophila to study the human genes associated with neurodegenerative diseases. This has added substantially to our understanding of the mechanisms leading to neurodegenerative diseases in humans. The isolation and characterization of Drosophila mutants, which display a variety of neurodegenerative phenotypes, also provide valuable insights into genes, pathways, and mechanisms causing neurodegeneration. So far only about two dozen such mutants have been described but already their characterization reveals an involvement of various cellular functions in neurodegeneration, ranging from preventing oxidative stress to RNA editing. Some of the isolated genes can already be associated with human neurodegenerative diseases and hopefully the isolation and characterization of more of these mutants, together with an analysis of homologous genes in vertebrate models, will provide insights into the genetic and molecular basis of human neurodegenerative diseases.

Animals↗
PubMed2006

Evolutionary origin of a plant mitochondrial group II intron from a reverse transcriptase/maturase-encoding ancestor.

Group II introns are widespread in plant cell organelles. In vivo, most if not all plant group II introns do not self-splice but require the assistance of proteinaceous splicing factors. In some cases, a splicing factor (also referred to as maturase) is encoded within the intronic sequence and produced by translation of the (excised) intron RNA. However, most present-day group II introns in plant organellar genomes do not contain open reading frames (ORFs) for splicing factors, and their excision may depend on proteins encoded by other organellar introns or splicing factors encoded in the nuclear genome. Whether or not the ancestors of all of these noncoding organellar introns originally contained ORFs for maturases is currently unknown. Here we show that a noncoding intron in the mitochondrial cox2 gene of seed plants is likely to be derived from an ancestral reverse transcriptase/maturase-encoding form. We detected remnants of maturase and reverse transcriptase sequences in the 2.7 kb cox2 intron of Ginkgo biloba, the only living species of an ancient gymnosperm lineage, suggesting that the intron originally harbored a splicing factor. This finding supports the earlier proposed hypothesis that the ancient group II introns that invaded organellar genomes were autonomous genetic entities in that they encoded the factor(s) required for their own excision and mobility.

Amino Acid Sequence↗
PubMed2025

Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling.

PURPOSE: Type I interferonopathy encompasses disorders marked by systemic inflammation and neurological involvement, arising from genetic mutations that result in the upregulation of type I IFN signaling through various mechanisms. Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs). METHODS: The IFIH1 R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from IFIH1 R779H-mutated iPSC-derived DCs. RESULTS: Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways. IFIH1 R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-α secretion. Among the DEGs, PML was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion from IFIH1 R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-α secretion from IFIH1 R779H-mutated DCs. CONCLUSION: Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.

Humans↗
PubMed2006

Neuroprotective effect of a chuk-me-sun-dan on neurons from ischemic damage and neuronal cell toxicity.

Chukmesundan (CMSD), composed of the following 8 medicinal herbs including Panex ginseng C.A. MEYER, Atractylodes macrocephala KOID, Poria cocos WOLF, Pinellia ternata BREIT, Brassica alba BOISS, Aconitum carmichaeli DEBX, Cynanchum atratum BGE and Cuscuta chinensis LAM. CMSD is being used in Korea for the treatment of various symptoms accompanying hypertension and cerebrovascular disorders. This study was carried out to examine the effects of CMSD on cultured primary neuron cell, cell cytotoxicity and lipid peroxidation in Abeta-treated cells. Cell death was enhanced by addition of Abeta. Pretreatment of CMSD attenuated in cell killing induced by Abeta. The protective effect of the CMSD water extracts on Abeta-induced neuronal death was also observed by lactate dehydrogenase assay using cultured astrocyte cells. Abeta-induced cell death was protected by the water extract of CMSD in a dose-dependent manner, and 25-50 microg/ml was the most effective concentration. CMSD has been also shown to protect primary cultured neurons from N-methyl-D: -aspartate receptor-mediated glutamate toxicity. It was in vivo evidenced that CMSD protects neurons against ischemia-induced cell death. Moreover, oral administration of CMSD into mice prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous CMSD was also confirmed by counting synapses in the hippocampal CA1 region. The presence of CMSD in neuron cultures rescued the neurons from nitrogen oxide (NO)-induced death. From these, it was suggested that CMSD may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.

Amyloid beta-Peptides↗
PubMed2001

The hyper IgM syndrome.

The hyper IgM syndrome is a rare, inherited immune deficiency disorder resulting from defects in the CD40 ligand/CD40-signaling pathway. X-linked hyper IgM is caused by defects in the CD40 ligand gene, while autosomal recessive hyper IgM is caused by defects in the CD40-activated RNA-editing enzyme, activation-induced cytidine deaminase, which is required for immunoglobulin isotype switching and somatic hypermutation in B cells. The loss of interaction between CD40 and its ligand in X-linked hyper IgM results in an impairment of T cell function, of B cell differentiation, and of monocyte function, while only B cell differentiation appears to be affected in autosomal recessive hyper IgM. With genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitely, to perform genetic screening, and to delineate the clinical manifestations of this syndrome. Further research may lead to novel and definitive therapeutic options for patients with hyper IgM syndrome.

CD40 Ligand↗
PubMed1994

Molecular biology of glutamate receptors.

The ligand-gated receptors for L-glutamate play a central role in acute neuronal degeneration. Recently cDNAs have been isolated for subunits of several glutamate receptor subtypes. By sequence homology all these subunits clearly belong to one large gene family. Several subfamilies exist and match roughly previously pharmacologically and electrophysiologically defined subtypes of glutamate receptors. Currently four genes (GluR A, B, C and D) are known that code for the AMPA subtypes of glutamate receptors. Recombinant expression of wild type and mutated sequences identified a critical residue in the putative TM2 channel-lining segment that controls Ca2+ ion permeability. The arginine (R) found in GluR B subunits at that position renders AMPA channels impermeable for Ca2+ ions, whereas glutamine (Q) containing GluR A, C and D subunits give rise to Ca2+ permeable channels. RNA editing converts the genomically encoded glutamine codon into the arginine codon found in GluR B cDNAs for the Q/R site. NMDA subtypes of glutamate receptors are formed after coexpression of the NR1 cDNA with a cDNA of the NR2 family. Depending on the member of the NR2 family used, NMDA receptors with different kinetical and pharmacological properties are generated. Common to all channels of these NMDA receptors is a high permeability for Ca2+ ions and a voltage dependent block by Mg2+ ions. All currently known NMDA receptor subunits have an asparagine at the Q/R homologous position. We found that this residue is critical for Mg2+ block and Ca2+ permeability of NMDA receptor channels.

Amino Acid Sequence↗
PubMed1993

Stimulation of protein synthesis in isolated pancreatic acini from chronically ethanol-fed rats is due to alterations in post-transcriptional regulation.

In an earlier study, we reported that isolation of acini from the pancreas of rats fed ethanol chronically, led to a 2- to 3-fold increase in the rate of protein synthesis compared to acini from rats fed the control diet. In the present study, we wanted to investigate whether the enhanced rate of protein synthesis was due to an increased rate of degranulation, reflecting a stimulation of cellular signal transduction processes, and/or to changes at the level of transcription/translation. The rate of degranulation was monitored by initially prelabelling the secretory proteins in vivo with [3H]leucine followed by determination of their fate in the intact tissue as well as in the subsequently isolated acini. The recovery of the label in isolated acini as a fraction of that incorporated into the tissue was similar for control and ethanol-fed groups, suggesting that ethanol feeding had no effect on the rate of degranulation during the isolation of acini. The rate of incorporation of [3H]uridine into total RNA was about 70% higher in acini from the ethanol-fed group as compared to the control group, suggesting a higher rate of transcription. However, the steady-state level of mRNA for trypsinogen, a representative digestive enzyme mRNA, showed only a moderate increase of 20% in acini from the ethanol-fed group compared to those from the intact tissue. These results suggest that the increased rate of protein synthesis in isolated acini from ethanol-fed rat pancreas is primarily due to post-transcriptional modifications.

Animals↗
PubMed1995

Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block.

CA2+-permeable glutamate receptors assembled from subunits containing a GLN residue at the RNA editing site in membrane domain 2 show strong inward rectification. In HEK 293 cells transfected with the kainate receptor subunit GluR6(Q), inward rectification is lost in outside-out patches, suggesting a role for diffusible, cytoplasmic factors. Inclusion of different polyamines in the internal solution restored inward rectification, whereas Mg2+ (1 mM) was inactive. Spermidine (Kd[0 mV] = 5.5 microM) was of higher affinity than spermidine (Kd[0 mV] = 25.4 microM) or putrescine (Kd[0 mV] = 1.2 mM). AMPA receptors assembled from GluRA(flip) showed even higher affinity for spermine (Kd[0 mV] = 1.5 microM). Analysis of the voltage dependence of whole-cell responses predicted intracellular free spermine and spermidine concentrations of 51 and 153 muM, respectively.

Calcium↗
PubMed1994

Biased (A-->I) hypermutation of animal RNA virus genomes.

RNA genomes evolve largely on the basis of single point mutations introduced by imprecise RNA polymerases, or by recombination. Clusters of certain transitions (biased hypermutations) were detected first in the genomes of persistent viruses, and in the past year have also been found in the genomes of lytic RNA viruses. A cellular RNA-modifying enzyme probably introduces the clustered transitions and thus contributes to the evolution of RNA viruses.

Adenosine↗
PubMed1993

Mammalian ionotropic glutamate receptors.

Exciting new milestones in glutamate receptor (GluR) channel research include the following: the cloning of N-methyl-D-aspartate (NMDA) receptors; delineation of molecular determinants for ion flow through glutamate-gated channels; the discovery that Ca2+ permeability of non-NMDA receptor channels is determined by RNA editing; the construction of antibodies and their use in immunocytochemical localizations of alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) receptor subunits in the rat brain; and the return to prominence of the high-affinity kainate site with the publication of cDNA sequences for subunits (GluR-5, -6, -7; KA-1, -2) constituting subtypes of this site. Major unresolved issues comprise the transmembrane topology and subunit stoichiometries of native receptor channels.

Amino Acid Sequence↗
PubMed2004

Group IB phospholipase A2 from Pseudonaja textilis.

Pseudonaja textilis, an Australian Elapid, is known to produce a highly toxic venom. Both protein profiling and N-terminal sequence analysis showed the presence of four new phospholipases A(2) in this venom. Besides being non-lethal, the phospholipase A(2) proteins were found to be moderately active enzymes and they showed procoagulant property. cDNA cloning and characterization indicated the presence of two isoforms of PLA(2) proteins in a single snake, each containing the "pancreatic loop," characteristic of group IB phospholipase A(2). The genomic cloning also confirmed the presence of two genes each containing four exons that are interrupted by three introns. Phylogenetic analysis showed that the venom group IB PLA(2) gene is primitive and could have evolved from the same ancestor as the mammalian and venom group IA PLA(2) genes. In the present study, we report that the Pt-PLA2 gene could be responsible for the production of PL1, 2, and 3 possibly via RNA editing process.

Amino Acid Sequence↗
PubMed2004

Proteolytic degradation of the nuclear isoform of uracil-DNA glycosylase occurs during the S phase of the cell cycle.

Uracil-DNA glycosylases are enzymes that remove uracil from DNA and initiate base-excision repair. These enzymes play a key role in maintaining genomic integrity by reducing the mutagenic events caused by G:C to A:T transition mutations. The recent finding that a family of RNA editing enzymes (APOBECs) can deaminate cytosine in DNA has raised the interest in these base-excision repair enzymes. This research focuses on the regulation of the nuclear isoform of uracil-DNA glycosylase, a 36000 Da protein that contains a unique 44 amino acid N-terminus. In synchronized HeLa cells, UDG1A protein levels decrease to barely detectable levels during the S phase of the cell cycle. Immunoblot analysis of immunoprecipitated or affinity-isolated UDG1A reveals ubiquitin-conjugated UDG1A when proteolysis is inhibited using N-acetyl-leu-leu-norleu-al or MG132, inhibitors of proteosomal dependent protein degradation. Transient transfection experiments, with histidine-tagged ubiquitin, were used to confirm that endogenous UDG1A is ubiquitinated in vivo. Addition of the nuclear export inhibitor, leptomycin B, prevents ubiquitination and degradation of UDG1A. This indicates that translocation from the nucleus may be a step in UDG1A turnover. Finally, UDG1A protein degradation is prevented when cells are incubated with the cyclin-dependent kinase inhibitor, roscovitine. These results suggest that protein phosphorylation and/or nuclear export participate in the post-translational regulation of UDG1A protein levels.

Cell Nucleus↗
PubMed2003

Serotonin and drug reward: focus on 5-HT2C receptors.

Pharmacological manipulation of the 5-hydroxytryptamine (5-HT; serotonin) system has long been associated with a regulation of feeding behaviour, however, the initial part of this article reviews evidence that central 5-HT systems similarly modulate reward-related behaviours, particularly drug reward. The second part of this article considers what we believe to be strong emerging pharmacological and genetic evidence that many of these effects are mediated through 5-HT(2C) receptor signalling mechanisms. Finally, we consider the potential for selective 5-HT(2C) agonists as therapies for substance abuse disorders and the medical implications for different 5-HT(2C) receptor isoforms generated by RNA editing.

Animals↗
PubMed2005

RNA silencing in Drosophila.

Knowledge of the role of RNA in affecting gene expression has expanded in the past several years. Small RNAs serve as homology guides to target messenger RNAs for destruction at the post-transcriptional level in the experimental technique known as RNA interference and in the silencing of some transgenes. These small RNAs are also involved in sequence-specific targeting of chromatin modifications for transcriptional silencing of transgenes, transposable elements, heterochromatin and some cases of Polycomb-mediated gene silencing. RNA silencing processes in Drosophila are described.

Animals↗
PubMed2006

Plant mitochondrial genes can be expressed from mRNAs lacking stop codons.

The mRNAs of the nad6 and ccmC genes of Arabidopsis and cauliflower were found to be processed upstream of the inframe stop codons. This result was confirmed by northern hybridization and by RT-PCR. There is no evidence that an alternative stop codon is created post-transcriptionally, either by RNA editing or by polyadenylation. The non-stop mRNAs are found in the high molecular weight polysomal fractions, suggesting that they are translated. Using antibodies directed against CcmC, the corresponding protein was detected in Arabidopsis mitochondrial extracts. These observations raise the question of how the plant mitochondrial translation system deals with non-stop mRNAs.

Arabidopsis↗
PubMed2006

Tissue-specific sensitivity to AID expression in transgenic mouse models.

Activation-induced cytidine deaminase (AID), an enzyme with homology to members of the APOBEC family, is involved in somatic hypermutation (SHM) of immunoglobulin (Ig) genes, either by direct deamination of DNA or by an indirect action through its putative RNA editing activity. AID is able to mutate both Ig-like reporter constructs and selected non-Ig genes in normal B cells and in other cells when ectopically overexpressed in mammalian cells and transgenic mice. However, in spite of the fact that in these transgenic animals AID activity was driven by an ubiquitous promoter, only T lymphomas and lung adenomas occurred. In the present work, we constructed three sets of transgenic mice in which AID was under the control of lck, HTLV-I and MMTV promoters, respectively. The lck/AID mice developed thymic lymphomas with variable but high efficiency, while no tumor was detected in HTLV-I/AID mice after two years of monitoring. Four MMTV/AID founder mice died with an atypical clinical picture, although no mammary tumor was found. These findings suggest that additional factors, present in thymocytes but not in other tissues or in lymphoid cells at different stages of differentiation, are needed for AID to fully manifest its tumorigenic potential in mouse. Alternatively, the display of full AID mutagenic and transforming activity could be related to the existence of physiologic DSBs which occur in both thymocytes and switching B cells.

Animals↗