title: Intrastriatal GDNF gene transfer by inducible lentivirus vectors protects dopaminergic neurons in a rat model of parkinsonism.
abstract: Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects on dopaminergic (DA) neurons both in vivo and in vitro. However, substantial evidence has shown that a long-term overexpression of GDNF gene is often associated with side effects. We previously improved tetracycline (Tet)-On lentivirus system carrying human GDNF (hGDNF) gene, and demonstrated that hGDNF gene expression was tightly regulated and functional in vitro. Here we further examined the efficiency and neuroprotection of Tet-On lentivirus-mediated hGDNF gene regulation in neural progenitor cells (NPCs) and a rat model of parkinsonism. The results showed that hGDNF gene expression was tightly regulated in transduced NPCs. Doxycycline (Dox)-induced hGDNF protected DA neurons from 6-hydroxydopamine (6-OHDA)-induced toxicity in vitro. Intrastriatal injections of Tet-On lentivirus vectors resulted in dramatically increased levels of hGDNF protein in the striatum of rats with Dox-drinking water, when compared to lentivirus-injected and saline-injected rats with normal drinking water, respectively. In addition, hGDNF protected nigral DA neurons and striatal DA fibers, and attenuated d-amphetamine-induced rotational asymmetry in the 6-OHDA lesioned rats. To the best of our knowledge, this is the first report that hGDNF gene transfer by Tet-On lentivirus vectors is tightly regulated in rat brain, and Dox-induced hGDNF is functional in neuroprotection of nigral DA neurons in a rat model of parkinsonism.
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Hao
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: Zhao
authors.affiliation: Department of Anatomy, Capital Medical University, Beijing 100069, China; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China. Electronic address: duanwm08@yahoo.com.
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Duan
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D003342:Corpus Striatum / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D005822:Genetic Vectors / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation; D009447:Neuroblastoma / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology* / Q000601:surgery*; D051381:Rats
chemical_list: D018663:Adrenergic Agents; D017077:Culture Media, Conditioned; D051100:Glial Cell Line-Derived Neurotrophic Factor; D049452:Green Fluorescent Proteins; D016627:Oxidopamine; D004318:Doxycycline
keywords: Dopaminergic neurons; Gene transfer; Glial cell line-derived neurotrophic factor; Lentivirus vectors; Parkinson's disease; Striatum