title: Activation of CNTF/CNTFRα signaling pathway by hRheb(S16H) transduction of dopaminergic neurons in vivo.
abstract: Ciliary neurotrophic factor (CNTF) is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor α (CNTFRα). It is still unclear whether the levels of CNTFRα change in the substantia nigra of Parkinson's disease (PD) patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc), suggesting that the support of CNTF/CNTFRα signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb), with an S16H mutation [hRheb(S16H)], significantly upregulated the levels of both CNTF and CNTFRα in dopaminergic neurons. Moreover, the hRheb(S16H)-activated CNTF/CNTFRα signaling pathway was protective against 1-methyl-4-phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFRα signaling pathway by specific gene delivery such as hRheb(S16H) may have therapeutic potential in the treatment of PD.
authors: School of Life Sciences, Institute of Life Science & Biotechnology, Kyungpook National University, Daegu, Korea; BK21 plus KNU Creative BioResearch Group, Institute of Life Science & Biotechnology, Kyungpook National University, Daegu, Korea.
authors: Kyoung Hoon
authors: KH
authors: Jeong
authors: Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors: Jin Han
authors: JH
authors: Nam
authors: Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea; Department of Biochemistry & Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
authors: Byung Kwan
authors: BK
authors: Jin
authors: School of Life Sciences, Institute of Life Science & Biotechnology, Kyungpook National University, Daegu, Korea; BK21 plus KNU Creative BioResearch Group, Institute of Life Science & Biotechnology, Kyungpook National University, Daegu, Korea; Institute of Life Science & Biotechnology, Kyungpook National University, Daegu, Korea; Brain Science and Engineering Institute, Kyungpook National University, Daegu, Korea.
authors: Sang Ryong
authors: SR
authors: Kim
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics*; D000066829:Neuroprotection / Q000187:drug effects / Q000235:genetics; D065842:Pars Compacta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D020934:Ciliary Neurotrophic Factor; D053739:Ciliary Neurotrophic Factor Receptor alpha Subunit; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D020559:Monomeric GTP-Binding Proteins; D015655:1-Methyl-4-phenylpyridinium