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

Abstract

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.

Salidroside protected against MPP+‐induced Parkinson's disease in PC12 cells by inhibiting inflammation, oxidative stress and cell apoptosis

“…Parkinson's disease (PD) is a progressive neurodegenerative disease with the characteristic pathological changes of mesencephalic substantia nigra dopaminergic neuron degeneration and necrosis [1,2]. PD patients exhibit a series of typical symptoms, such as tremor, muscle stiffness, and movement disorders [3].…”

RNA-Sequencing Reveals Similarities and Differences in Gene Expression in Vulnerable Brain Tissues of Alzheimer’s and Parkinson’s Diseases

“…Increased expression of NRN1 promotes maturation of synapses in hippocampal neurons prepared from Tg2576 mice, and Neuritin infusion into Tg2576 mice normalizes synaptic plasticity in hippocampal slices [ 20 ]. NRN1 expression is increased by glial cell-derived neurotrophic factor (GDNF, [ 20 ]), and GDNF improves survival of nigral dopamine neurons in a chronic model of Parkinson’s disease (MitoPark mice, [ 21 ]). NMNAT2 : (GEIs PD = 4.57; AD = 0.24).…”

Outside in: Unraveling the Role of Neuroinflammation in the Progression of Parkinson's Disease

“…The neuroprotective and neurorestorative effect of GDNF has been shown in numerous neurotoxic PD models including mouse, rat ( 99 – 101 ) and no-human primates ( 102 ). In a recent study, Chen et al demonstrated that GDNF derived from macrophages diminished the loss of dopaminergic neurons and improved motor symptoms in a mouse model of PD ( 103 ). In this study, bone marrow hematopoietic stem cells were transduced with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into the MitoPark mice ( 103 , 104 ).…”

“…In a recent study, Chen et al demonstrated that GDNF derived from macrophages diminished the loss of dopaminergic neurons and improved motor symptoms in a mouse model of PD ( 103 ). In this study, bone marrow hematopoietic stem cells were transduced with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into the MitoPark mice ( 103 , 104 ). These genetically modified macrophages were able to infiltrate the midbrain of MitoPark mice, but not control littermates.…”

“…These genetically modified macrophages were able to infiltrate the midbrain of MitoPark mice, but not control littermates. This was accompanied with GDNF secretion, an improvement in motor and non-motor symptoms and a reduction of dopaminergic neurons loss in the SNpc and its axonal terminals in the striatum ( 103 ). The mechanisms that are involved in the neuroprotective effect of GDNF are still unknown.…”