GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice
Autor: | Cori Ballard, Xiuhua Li, Yusheng Qian, Suzette D. Laing, K.C. Biju, Zhixu He, Guo Ge, Senlin Li, Eliezer Masliah, Cang Chen, Jingwei Liu, Robert A. Clark, Jason C. O'Connor |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cell Survival Gene Expression lcsh:Medicine Substantia nigra Motor Activity Neuroprotection Article 03 medical and health sciences Mice 0302 clinical medicine Parkinsonian Disorders Dopamine Neurotrophic factors Cell Line Tumor Glial cell line-derived neurotrophic factor medicine Animals Humans Glial Cell Line-Derived Neurotrophic Factor lcsh:Science Neuroinflammation Multidisciplinary biology business.industry Dopaminergic Neurons Macrophages lcsh:R Neurotoxicity Hematopoietic Stem Cell Transplantation Genetic Therapy medicine.disease 3. Good health Transplantation 030104 developmental biology nervous system Cancer research biology.protein lcsh:Q business 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-16 (2018) Scientific Reports |
ISSN: | 2045-2322 |
Popis: | Glial cell line-derived neurotrophic factor (GDNF) is the most potent neuroprotective agent tested in cellular and animal models of Parkinson’s disease (PD). However, CNS delivery of GDNF is restricted by the blood-brain barrier (BBB). Using total body irradiation as transplant preconditioning, we previously reported that hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated gene therapy could deliver GDNF to the brain to prevent degeneration of nigrostriatal dopamine (DA) neurons in an acute murine neurotoxicity model. Here, we validate this therapeutic approach in a chronic progressive PD model – the MitoPark mouse, with head shielding to avoid inducing neuroinflammation and compromising BBB integrity. Bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into MitoPark mice exhibiting well developed PD-like impairments. Transgene-expressing macrophages infiltrated the midbrains of MitoPark mice, but not normal littermates, and delivered GDNF locally. Macrophage GDNF delivery markedly improved both motor and non-motor symptoms, and dramatically mitigated the loss of both DA neurons in the substantia nigra and tyrosine hydroxylase-positive axonal terminals in the striatum. Our data support further development of this HSCT-based macrophage-mediated GDNF delivery approach in order to address the unmet need for a disease-modifying therapy for PD. |
Databáze: | OpenAIRE |
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