GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice

Cang Chen, Xiuhua Li, Guo Ge, Jingwei Liu, K. C. Biju, Suzette D. Laing, Yusheng Qian, Cori Ballard, Zhixu He, Eliezer Masliah, Robert A. Clark, Jason C. O'Connor, Senlin Li

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32 Scopus citations


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.

Original languageEnglish (US)
Article number5460
JournalScientific reports
Issue number1
StatePublished - Dec 1 2018

ASJC Scopus subject areas

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