title: Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson's disease.
abstract: Although neurotrophic factors have long been recognized as potent agents for protecting against neuronal degeneration, clinical success in treating Parkinson's disease and other neurodegenerative disorders has been hindered by difficulties in delivery of trophic factors across the blood brain barrier (BBB). Bone marrow hematopoietic stem cell-based gene therapy is emerging as a promising tool for overcoming drug delivery problems, as myeloid cells can cross the BBB and are recruited in large numbers to sites of neurodegeneration, where they become activated microglia that can secrete trophic factors. We tested the efficacy of bone marrow-derived microglial delivery of neurturin (NTN) in protecting dopaminergic neurons against neurotoxin-induced death in mice. Bone marrow cells were transduced ex vivo with lentivirus expressing the NTN gene driven by a synthetic macrophage-specific promoter. Infected bone marrow cells were then collected and transplanted into recipient animals. Eight weeks after transplantation, the mice were injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropuridine (MPTP) for seven days to induce dopaminergic neurodegeneration. Microglia-mediated NTN delivery dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and their terminals in the striatum. Microglia-mediated NTN delivery also induced significant recovery of synaptic marker staining in the striatum of MPTP-treated animals. Functionally, NTN treatment restored MPTP-induced decline in general activity, rearing behavior, and food intake. Thus, bone marrow-derived microglia can serve as cellular vehicles for sustained delivery of neurotrophic factors capable of mitigating dopaminergic injury.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
authors.forename: K C
authors.initials: KC
authors.lastname: Biju
authors.forename: Rene A
authors.initials: RA
authors.lastname: Santacruz
authors.forename: Cang
authors.initials: C
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Jiemin
authors.initials: J
authors.lastname: Yao
authors.forename: Sara L
authors.initials: SL
authors.lastname: Rohrabaugh
authors.forename: Robert A
authors.initials: RA
authors.lastname: Clark
authors.forename: James L
authors.initials: JL
authors.lastname: Roberts
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Phillips
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Imam
authors.forename: Senlin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D059290:Dopaminergic Neurons / Q000473:pathology*; D015316:Genetic Therapy; D016086:Lentivirus / Q000235:genetics; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism* / Q000637:transplantation; D009043:Motor Activity; D009410:Nerve Degeneration / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D051101:Neurturin / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D051101:Neurturin; C495056:Nrtn protein, mouse