Host to graft propagation of α-synuclein in Parkinson’s disease: intra-nigral versus intra-striatal transplantation.
Résumé
Parkinson´s disease (PD) is a neurodegenerative disorder characterized by resting tremors, rigidity, and hypokinesia. At the neuropathological level, PD is characterized by the degeneration of nigro-striatal dopaminergic (DA) neurons and by an abnormal accumulation of aggregated α-synuclein (α-syn), the main protein component of Lewy bodies. Intrastriatal transplantation of DA neurons from fetal ventral mesencephalic (VM) tissue in PD patients have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted DA neurons can innervate the denervated striatum, improve striatal DA levels and in some patient lead to clinical improvements. However, following autopsy, 10-22 years after transplantation, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. The goal of our project is to investigate the propagation of α-syn from host to graft by comparing two transplantation sites, the substantia nigra (SN) and the striatum. Our hypothesis is that the striatum, which is not the natural site of DA neurons, represents an unfavorable environment for transplanted neurons, making DA neurons more vulnerable to the disease process. For this purpose, we set up a mouse model of PD by viral injection of AAV2-hα-synuclein A53T into the SNc of C57BL/6 WT mice. Four weeks post viral injection, we already observed a unilateral motor deficit in cylinder test. Our results show an accumulation of α-syn associated with a nigral DA degeneration from 6 weeks post viral injection up to 12 weeks. After model validation, DA progenitors from VM of β-actin GFP mouse embryo were grafted either in the SN or the striatum of lesioned mice. At different time points after grafting, we quantified the presence of α-syn in the graft. Our preliminary results, in both nigral and striatal grafts locations, show that the accumulation of human α-syn is higher at 5 month-post grafting compared to 1 month. Yet, from 2-month post transplantation, it appears that the amount of α-syn is higher in grafts located in the SN. This may be due to the greater viral load in the SN, which is the virus injection site. Ongoing experiments are underway to determine the impact of the viral injection site on host to graft α-syn propagation.