Objective: The overall goal is to produce a rat model of Parkinson’s disease (PD), which reproduces progressive pathological changes, while displaying profound neuronal cell loss and behavior deficit. In this experiment, we aimed to determine whether the addition of preformed α-syn fibrils, injected into the striatum, could worsen the pathology observed using a low dose of α-synuclein (α-syn) adeno-associated virus (AAV) injection in the substantia nigra.

Background: α-syn is known to play a role in both familial and idiopathic PD. Thus, virus-mediated expression of α-syn has been used for over a decade to try to model PD in rodents. Although AAV-α-syn-injected animals develop synucleinopathy, neuronal degeneration and behavior impairments are variable. It is therefore important to improve the AAV-α-syn model to allow more profound and consistent nigral dopamine neuron degeneration.

Methods: Rats received bilateral nigral injections of AAV α-syn coding for expression of human α-syn, while others were left intact. All animals were then injected in the right striatum with preformed α-syn fibrils. Animal behavior was assessed using cylinder and stepping tests. The brains were perfused at different time points and processed for immunochemistry in order to assess dopaminergic cell survival.

Results: A loss of 35% in tyrosine hydroxylase (TH) cells was observed after 3weeks in the nigra of AAV-α-syn injected animals. At that stage, the addition of fibrils by intra-striatal injection did not cause any further cell loss compared to AAV-α-syn alone. However, when assessed at 24 weeks, there was over 70% TH cell loss on the side receiving AAV-α-syn plus fibrils, which was significantly different from AAV-α-syn or fibril injection alone (respectively, around 50 and 40%). These results were in accordance with the behavior data. Indeed, contralateral side showed impaired performances, in stepping and cylinder tests, 24weeks after the combined injections. No significant impairment in motor functions was observed up to 18 weeks, suggesting that the animals were able to compensate for the mild neuronal loss up to that time-point.

Conclusions: From these preliminary results, we can conclude that addition of preformed α-syn fibrils, injected into the striatum,worsens the pathology induced by low-dose AAV-mediated over expression of α-syn, as demonstrated by both nigral TH-positive cell loss loss and motor dysfunction.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pre-formed-fibrils-injection-worsen-pathology-caused-by-aav-mediated-over-expression-of-synuclein/