title: Induction of GDNF and BDNF by hRheb(S16H) transduction of SNpc neurons: neuroprotective mechanisms of hRheb(S16H) in a model of Parkinson's disease.
abstract: The transduction of dopaminergic (DA) neurons with human ras homolog enriched in brain, which has a S16H mutation [hRheb(S16H)] protects the nigrostriatal DA projection in the 6-hydroxydopamine (6-OHDA)-treated animal model of Parkinson's disease (PD). However, it is still unclear whether the expression of active hRheb induces the production of neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), which are involved in neuroprotection, in mature neurons. Here, we show that transduction of nigral DA neurons with hRheb(S16H) significantly increases the levels of phospho-cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), GDNF, and BDNF in neurons, which are attenuated by rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Moreover, treatment with specific neutralizing antibodies for GDNF and BDNF reduced the protective effects of hRheb(S16H) against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity. These results show that activation of hRheb/mTORC1 signaling pathway could impart to DA neurons the important ability to continuously produce GDNF and BDNF as therapeutic agents against PD.
authors.affiliation: Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, 130-701, Korea.
authors.forename: Jin Han
authors.initials: JH
authors.lastname: Nam
authors.forename: Eunju
authors.initials: E
authors.lastname: Leem
authors.forename: Min-Tae
authors.initials: MT
authors.lastname: Jeon
authors.forename: Kyoung Hoon
authors.initials: KH
authors.lastname: Jeong
authors.forename: Jeen-Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Un Ju
authors.initials: UJ
authors.lastname: Jung
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kholodilov
authors.forename: Robert E
authors.initials: RE
authors.lastname: Burke
authors.forename: Byung Kwan
authors.initials: BK
authors.lastname: Jin
authors.forename: Sang Ryong
authors.initials: SR
authors.lastname: Kim
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis*; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000378:metabolism* / Q000517:prevention & control; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009479:Neuropeptides; D018696:Neuroprotective Agents; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D020559:Monomeric GTP-Binding Proteins