Neuronal specificity of α-synuclein toxicity and effect of Parkin co-expression in primates

Abstract

Recombinant adeno-associated viral (rAAV) vector-mediated overexpression of α-synuclein (αSyn) protein has been shown to cause neurodegeneration of the nigrostriatal dopaminergic pathway in rodents and primates. Using serotype-2 rAAV vectors, we recently reported the protective effect of Parkin on αSyn-induced nigral dopaminergic neurodegeneration in a rat model. Here we investigated the neuronal specificity of αSyn toxicity and the effect of Parkin co-expression in a primate model. We used another serotype (type-1) of AAV vector that was confirmed to deliver genes of interest anterogradely and retrogradely to neurons in rats. The serotype-1 rAAV (rAAV1) carrying αSyn cDNA (rAAV1-αSyn), and a cocktail of rAAV1-αSyn and rAAV1 carrying parkin cDNA (rAAV1-parkin) were unilaterally injected into the striatum of macaque monkeys, resulting in protein expression in striatonigral GABAergic and nigrostriatal dopaminergic neurons. Injection of rAAV1-αSyn alone decreased tyrosine hydroxylase immunoreactivity in the striatum compared with the contralateral side injected with a cocktail of rAAV1-αSyn and rAAV1-parkin. Immunostaining of striatonigral GABAergic neurons was similar on both sides. Overexpression of Parkin in GABAergic neurons was associated with less accumulation of αSyn protein and/or phosphorylation at Ser129 residue. Our results suggest that the toxicity of accumulated αSyn is not induced in non-dopaminergic neurons and that the αSyn-ablating effect of Parkin is exerted in virtually all neurons in primates.