Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyotrophic lateral sclerosis (ALS) is a fatal disorder whose etiology and pathogenesis remain unknown. Recent studies, however, have demonstrated the presence of inflammatory infiltrates within ALS spinal cord and suggested the possibility of an immune-mediated process in motor neuron degeneration. We have analyzed the diversity of T-cells in the spinal cord in ALS. Reverse transcriptase polymerase chain reaction (RT-PCR) with variable (V) region sequence specific oligonucleotide primers was used to amplify T-cell receptor (TCR)BV transcripts from spinal cords obtained at autopsy from patients with ALS, patients who died without inflammatory disease of the central nervous system, brains from patients with ALS, and brains from patients who died with inflammatory CNS disease. Sequencing was then performed on the amplified transcripts. An overall increase in the level of TCRBV 2 transcripts was detected in ALS specimens when compared to controls. This result was independent of the HLA genotype of the individual. Furthermore, enrichment of TCRBV2-positive T cells could be demonstrated in cerebrospinal fluid derived from patients with ALS, using PCR analysis and a T cell stimulation assay with toxic shock syndrome toxin-1 (TSST-1), a Vbeta2-specific superantigen. Our results suggest that an immunological process involving the specific expansion of Vbeta2 TCR-positive T-cells may be important in the pathogenesis of ALS.
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PMID:T cell receptor BV gene rearrangements in the spinal cords and cerebrospinal fluid of patients with amyotrophic lateral sclerosis. 1052 6

Sequences resembling those of human enterovirus type B sequences have been associated with motor neurone disease/amyotrophic lateral sclerosis. In a previous study we detected enteroviral sequences in spinal cord/brain stem from cases of motor neurone disease/amyotrophic lateral sclerosis, but not controls. Adjacent tissue sections to two of those strongly positive for these sequences by reverse-transcriptase polymerase chain reaction were analyzed by in situ hybridization with digoxigenin-labelled virus-specific antisense riboprobes. In one case, a female aged 83 showing 12 month rapid progressive disease, signal was specifically localized to cells identifiable as motor neurones of the anterior horn. In another case, a male aged 63 with a 60-month history of progressive muscle weakness, dysarthia, dyspnoea and increased tendon reflexes, signal was located to neurones in the gracile/cuneate nuclei of the brain stem tissue block that had been analyzed. This case showed loss of neurones in the anterior horn of the spinal cord by histopathologic examination which would account for clinical signs of motor neurone disease/amyotrophic lateral sclerosis. Dysfunction of the gracile/cuneate nuclei might have been masked by the paralytic disease. These structures are adjacent to the hypoglossal nuclei, and suggest either localised dissemination from hypoglossal nuclei or a possible route of dissemination of infection through the brainstem to the hypoglossal nuclei. These findings provide further evidence for the possible involvement of enteroviruses in motor neurone disease/amyotrophic lateral sclerosis.
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PMID:Evidence for neuronal localisation of enteroviral sequences in motor neurone disease/amyotrophic lateral sclerosis by in situ hybridization. 1520 80

Reverse transcriptase has been detected in the serum of HIV-negative patients with amyotrophic lateral sclerosis (ALS). An ALS-like disorder in HIV-positive patients can remit with antiretroviral therapy. Using the product enhanced assay technique, we measured reverse transcriptase activity in the serum and CSF of 23 HIV-negative patients with ALS and 21 neurologic disease controls. Results for CSF were not significant, whereas reverse transcriptase was detected in 56% of ALS sera vs 19% of controls.
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PMID:A controlled study of reverse transcriptase in serum and CSF of HIV-negative patients with ALS. 1753 52

The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In particular, p25/Cdk5 has been shown to produce hyperphosphorylated tau, neurofibrillary tangles as well as aberrant amyloid precursor protein processing found in AD. Neuroinflammation has been observed alongside the pathogenic process in these neurodegenerative diseases, however the precise mechanism behind the induction of neuroinflammation and the significance in the AD pathogenesis has not been fully elucidated. In this report, we uncover a novel pathway for p25-induced neuroinflammation where p25 expression induces an early trigger of neuroinflammation in vivo in mice. Lipidomic mass spectrometry, in vitro coculture and conditioned media transfer experiments show that the soluble lipid mediator lysophosphatidylcholine (LPC) is released by p25 overexpressing neurons to initiate astrogliosis, neuroinflammation and subsequent neurodegeneration. Reverse transcriptase PCR and gene silencing experiments show that cytosolic phospholipase 2 (cPLA2) is the key enzyme mediating the p25-induced LPC production and cPLA2 upregulation is critical in triggering the p25-mediated inflammatory and neurodegenerative process. Together, our findings delineate a potential therapeutic target for the reduction of neuroinflammation in neurodegenerative diseases including AD.
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PMID:Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration. 2226

ALS-8112 is the parent molecule of ALS-8176, a first-in-class nucleoside analog prodrug effective in the clinic against respiratory syncytial virus (RSV) infection. The antiviral activity of ALS-8112 is mediated by its 5'-triphosphate metabolite (ALS-8112-TP, or 2'F-4'ClCH2-cytidine triphosphate) inhibiting the RNA polymerase activity of the RSV L-P protein complex through RNA chain termination. Four amino acid mutations in the RNA-dependent RNA polymerase (RdRp) domain of L (QUAD: M628L, A789V, L795I, and I796V) confer in vitro resistance to ALS-8112-TP by increasing its discrimination relative to natural CTP. In this study, we show that the QUAD mutations specifically recognize the ClCH2 group of ALS-8112-TP. Among the four mutations, A789V conferred the greatest resistance phenotype, which was consistent with its putative position in the active site of the RdRp domain. AZ-27, a non-nucleoside inhibitor of RSV, also inhibited the RdRp activity, with decreased inhibition potency in the presence of the Y1631H mutation. The QUAD mutations had no effect on the antiviral activity of AZ-27, and the Y1631H mutation did not significantly increase the discrimination of ALS-8112-TP. Combining ALS-8112 with AZ-27 in vitro resulted in significant synergistic inhibition of RSV replication. Overall, this is the first mechanistic study showing a lack of cross-resistance between mutations selected by different classes of RSV polymerase inhibitors acting in synergy, opening the door to future potential combination therapies targeting different regions of the L protein.
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PMID:Biochemical Effect of Resistance Mutations against Synergistic Inhibitors of RSV RNA Polymerase. 2716 48

Worldwide, respiratory syncytial virus (RSV) causes severe disease in infants, the elderly, and immunocompromised people. No vaccine or effective antiviral treatment is available. RSV is a member of the non-segmented, negative-strand (NNS) group of RNA viruses and relies on its RNA-dependent RNA polymerase to transcribe and replicate its genome. Because of its essential nature and unique properties, the RSV polymerase has proven to be a good target for antiviral drugs, with one compound, ALS-8176, having already achieved clinical proof-of-concept efficacy in a human challenge study. In this article, we first provide an overview of the role of the RSV polymerase in viral mRNA transcription and genome replication. We then review past and current approaches to inhibiting the RSV polymerase, including use of nucleoside analogs and non-nucleoside inhibitors. Finally, we consider polymerase inhibitors that hold promise for treating infections with other NNS RNA viruses, including measles and Ebola.
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PMID:New antiviral approaches for respiratory syncytial virus and other mononegaviruses: Inhibiting the RNA polymerase. 2757 93