Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients
1Department of Neurosciences, Lerner Research Institute, Cleveland, 2Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, OH, USA and 3Department of Psychiatry, Kennedy Center for Human Development, Vanderbilt University, Nashville, TN, USA
Correspondence to: Bruce D. Trapp, PhD, Department of Neurosciences/NC30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA E-mail: trappb{at}ccf.org
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, CNTFR
, LIFRß 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.
Key Words: multiple sclerosis; gene expression; CNTF; neuroprotection
Abbreviations: MS, Multiple sclerosis; CNTF, ciliary neurotrophic factor; LIF, leukaemia inhibitory factor; FDR, false discovery rate
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Received March 16, 2007. Revised July 20, 2007. Accepted August 6, 2007.
*Present address: Oak Clinic for MS Research at Kent State University, Kent, OH, USA
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