Host-to-graft Propagation of α-synuclein in a Mouse Model of Parkinson's Disease: Intranigral Versus Intrastriatal Transplantation.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies. Ectopic transplantation of human fetal ventral mesencephalic DA neurons into the striatum of PD patients have provided proof-of-principle for the cell replacement strategy in this disorder. However, 10 to 22 y after transplantation, 1% to 27% of grafted neurons contained α-syn aggregates similar to those observed in the host brain. We hypothesized that intrastriatal grafts are more vulnerable to α-syn propagation because the striatum is not the ontogenic site of nigral DA neurons and represents an unfavorable environment for transplanted neurons. Here, we compared the long-term host-to-graft propagation of α-syn in 2 transplantation sites: the SNpc and the striatum. METHODS: Two mouse models of PD were developed by injecting adeno-associated-virus2/9-human α-syn A53T into either the SNpc or the striatum of C57BL/6 mice. Mouse fetal ventral mesencephalic DA progenitors were grafted into the SNpc or into the striatum of SNpc or striatum of α-syn injected mice, respectively. RESULTS: First, we have shown a degeneration of the nigrostriatal pathway associated with motor deficits after nigral but not striatal adeno-associated-virus-hαsyn A53T injection. Second, human α-syn preferentially accumulates in striatal grafts compared to nigral grafts. However, no differences were observed for phosphorylated α-syn, a marker of pathological α-syn aggregates. CONCLUSIONS: Taken together, our results suggest that the ectopic site of the transplantation impacts the host-to-graft transmission of α-syn.

Long-Term Evaluation of Intranigral Transplantation of Human iPSC-Derived Dopamine Neurons in a Parkinson's Disease Mouse Model.

Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). One strategy for treating PD is transplantation of DA neuroblasts. Significant advances have been made in generating midbrain DA neurons from human pluripotent stem cells. Before these cells can be routinely used in clinical trials, extensive preclinical safety studies are required. One of the main issues to be addressed is the long-term therapeutic effectiveness of these cells. In most transplantation studies using human cells, the maturation of DA neurons has been analyzed over a relatively short period not exceeding 6 months. In present study, we generated midbrain DA neurons from human induced pluripotent stem cells (hiPSCs) and grafted these neurons into the SNpc in an animal model of PD. Graft survival and maturation were analyzed from 1 to 12 months post-transplantation (mpt). We observed long-term survival and functionality of the grafted neurons. However, at 12 mpt, we observed a decrease in the proportion of SNpc DA neuron subtype compared with that at 6 mpt. In addition, at 12 mpt, grafts still contained immature neurons. Our results suggest that longer-term evaluation of the maturation of neurons derived from human stem cells is mandatory for the safe application of cell therapy for PD.

Better Outcomes with Intranigral versus Intrastriatal Cell Transplantation: Relevance for Parkinson's Disease.

Intrastriatal embryonic ventral mesencephalon grafts have been shown to integrate, survive, and reinnervate the host striatum in clinical settings and in animal models of Parkinson's disease. However, this ectopic location does not restore the physiological loops of the nigrostriatal pathway and promotes only moderate behavioral benefits. Here, we performed a direct comparison of the potential benefits of intranigral versus intrastriatal grafts in animal models of Parkinson's disease. We report that intranigral grafts promoted better survival of dopaminergic neurons and that only intranigral grafts induced recovery of fine motor skills and normalized cortico-striatal responses. The increase in the number of toxic activated glial cells in host tissue surrounding the intrastriatal graft, as well as within the graft, may be one of the causes of the increased cell death observed in the intrastriatal graft. Homotopic localization of the graft and the subsequent physiological cell rewiring of the basal ganglia may be a key factor in successful and beneficial cell transplantation procedures.