Higher alpha-Synuclein aggregate density does not lead to more severe dopaminergic cell loss in the AAV-mediated overexpression model of Parkinson’s disease: A time-course study

Pathological intracellular aggregation of alpha-synuclein (a-syn) is the hallmark of Parkinson’s disease (PD). Our aim is to explore the outcomes of long-term a-syn pathology with its functional correlates in the PD model by AAV (adeno-associated virus)-mediated a-syn overexpression in substantia nigra (SN). Female Wistar rats (220-260 g) received a unilateral injection of AAV-human-a-syn or green fluorescent protein (GFP) gene into the SN. The animals were tested for motor functions with cylinder test at 8, 12 weeks or 9 months post-injection. The intensity of a-syn accumulation or GFP in striatum and dopaminergic neuronal loss in SN, dopaminergic terminal loss in striatum and synaptic integrity were analyzed by a-syn, GFP, tyrosine hydroxylase (TH) and synaptophsin immunohistochemistry, respectively. At all time-points, AAV-human-a-syn injected animals displayed more motor dysfunction and TH-positive cell loss compared to AAV-GFP injected group. A-syn immunoreactivity was present in the nigral neurons as well as the striatal terminals in all animals that received AAV-a-syn. Striatal TH density analysis showed a decrease in both 12-weeks and 9 months a-syn groups compared to controls. However, TH-positive neuron count was lower in 9-months group compared to 12-weeks group. Hence, the motor performance of 9-month group showed an improvement which may be a sign of a compensatory mechanisms against a-syn-induced neurodegeneration. The findings of this study implicate that higher a-syn density in SN does not always lead to worse motor function or more severe dopaminergic cell loss. This may support the hypothesis that a-syn aggregates are the end-product of a cellular defense mechanism rather than being causative pathology.