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 alpha-synuclein (alpha-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 alpha-syn aggregates similar to those observed in the host brain. We hypothesized that intrastriatal grafts are more vulnerable to alpha-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 alpha-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 alpha-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 alpha-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-h alpha syn A53T injection. Second, human alpha-syn preferentially accumulates in striatal grafts compared to nigral grafts. However, no differences were observed for phosphorylated alpha-syn, a marker of pathological alpha-syn aggregates. Conclusions. Taken together, our results suggest that the ectopic site of the transplantation impacts the host-to-graft transmission of alpha-syn.