Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. 2007

Ranjan Dutta, and Jennifer McDonough, and Ansi Chang, and Lakshman Swamy, and Alan Siu, and Grahame J Kidd, and Richard Rudick, and Karoly Mirnics, and Bruce D Trapp
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Neuronal and axonal degeneration results in irreversible neurological disability in multiple sclerosis (MS) patients. A number of adaptive or neuroprotective mechanisms are thought to repress neurodegeneration and neurological disability in MS patients. To investigate possible neuroprotective pathways in the cerebral cortex of MS patients, we compared gene transcripts in cortices of six control and six MS patients. Out of 67 transcripts increased in MS cortex nine were related to the signalling mediated by the neurotrophin ciliary neurotrophic factor (CNTF). Therefore, we quantified and localized transcriptional (RT-PCR, in situ hybridization) and translational (western, immunohistochemistry) products of CNTF-related genes. CNTF-receptor complex members, CNTFRalpha, LIFRbeta and GP130, were increased in MS cortical neurons. CNTF was increased and also expressed by neurons. Phosphorylated STAT3 and the anti-apoptotic molecule, Bcl2, known down stream products of CNTF signalling were also increased in MS cortical neurons. We hypothesize that in response to the chronic insults or stress of the pathogenesis of multiple sclerosis, cortical neurons up regulate a CNTF-mediated neuroprotective signalling pathway. Induction of CNTF signalling and the anti-apoptotic molecule, Bcl2, thus represents a compensatory response to disease pathogenesis and a potential therapeutic target in MS patients.

UI MeSH Term Description Entries
D009044 Motor Cortex Area of the FRONTAL LOBE concerned with primary motor control located in the dorsal PRECENTRAL GYRUS immediately anterior to the central sulcus. It is comprised of three areas: the primary motor cortex located on the anterior paracentral lobule on the medial surface of the brain; the premotor cortex located anterior to the primary motor cortex; and the supplementary motor area located on the midline surface of the hemisphere anterior to the primary motor cortex. Brodmann Area 4,Brodmann Area 6,Brodmann's Area 4,Brodmann's Area 6,Premotor Cortex and Supplementary Motor Cortex,Premotor and Supplementary Motor Cortices,Anterior Central Gyrus,Gyrus Precentralis,Motor Area,Motor Strip,Precentral Gyrus,Precentral Motor Area,Precentral Motor Cortex,Premotor Area,Premotor Cortex,Primary Motor Area,Primary Motor Cortex,Secondary Motor Areas,Secondary Motor Cortex,Somatic Motor Areas,Somatomotor Areas,Supplementary Motor Area,Area 4, Brodmann,Area 4, Brodmann's,Area 6, Brodmann,Area 6, Brodmann's,Area, Motor,Area, Precentral Motor,Area, Premotor,Area, Primary Motor,Area, Secondary Motor,Area, Somatic Motor,Area, Somatomotor,Area, Supplementary Motor,Brodmann's Area 6s,Brodmanns Area 4,Brodmanns Area 6,Central Gyrus, Anterior,Cortex, Motor,Cortex, Precentral Motor,Cortex, Premotor,Cortex, Primary Motor,Cortex, Secondary Motor,Cortices, Secondary Motor,Gyrus, Anterior Central,Gyrus, Precentral,Motor Area, Precentral,Motor Area, Primary,Motor Area, Secondary,Motor Area, Somatic,Motor Areas,Motor Cortex, Precentral,Motor Cortex, Primary,Motor Cortex, Secondary,Motor Strips,Precentral Motor Areas,Precentral Motor Cortices,Premotor Areas,Primary Motor Areas,Primary Motor Cortices,Secondary Motor Area,Secondary Motor Cortices,Somatic Motor Area,Somatomotor Area,Supplementary Motor Areas
D009103 Multiple Sclerosis An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903) MS (Multiple Sclerosis),Multiple Sclerosis, Acute Fulminating,Sclerosis, Disseminated,Disseminated Sclerosis,Sclerosis, Multiple
D009414 Nerve Growth Factors Factors which enhance the growth potentialities of sensory and sympathetic nerve cells. Neurite Outgrowth Factor,Neurite Outgrowth Factors,Neuronal Growth-Associated Protein,Neuronotrophic Factor,Neurotrophic Factor,Neurotrophic Factors,Neurotrophin,Neurotrophins,Growth-Associated Proteins, Neuronal,Neuronal Growth-Associated Proteins,Neuronotrophic Factors,Neurotrophic Protein,Neurotrophic Proteins,Proteins, Neuronal Growth-Associated,Factor, Neurite Outgrowth,Factor, Neuronotrophic,Factor, Neurotrophic,Factors, Nerve Growth,Factors, Neurite Outgrowth,Factors, Neuronotrophic,Factors, Neurotrophic,Growth Associated Proteins, Neuronal,Growth-Associated Protein, Neuronal,Neuronal Growth Associated Protein,Neuronal Growth Associated Proteins,Outgrowth Factor, Neurite,Outgrowth Factors, Neurite,Protein, Neuronal Growth-Associated
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014157 Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Transcription Factor,Factor, Transcription,Factors, Transcription
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015854 Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins. Receptor Up-Regulation,Upregulation,Up-Regulation (Physiology),Up Regulation
D050796 STAT3 Transcription Factor A signal transducer and activator of transcription that mediates cellular responses to INTERLEUKIN-6 family members. STAT3 is constitutively activated in a variety of TUMORS and is a major downstream transducer for the CYTOKINE RECEPTOR GP130. APRF Transcription Factor,Acute-Phase Response Factor,IL6-Response Factor,LIF-Response Factor,STAT3 Protein,STAT3a Transcription Factor,STAT3b Transcription Factor,Signal Transducer and Activator of Transcription 3,Stat3alpha Transcription Factor,Stat3beta Transcription Factor,Acute Phase Response Factor,IL6 Response Factor,LIF Response Factor,Response Factor, Acute-Phase,Transcription Factor, APRF,Transcription Factor, STAT3,Transcription Factor, STAT3a,Transcription Factor, STAT3b,Transcription Factor, Stat3alpha,Transcription Factor, Stat3beta

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