Motor Deficits upon Alpha-Synuclein Expression in the Nigrostriatal System Are Due to a Loss of Dopaminergic Vesicles and Reduced Dopamine Release at an early Stage of Neurodegeneration

Alpha-synuclein is linked to both sporadic and familial forms of Parkinson's disease. The protein represents the major component of Lewy bodies – one of the hallmarks of the disease. Additionally, several point mutations and locus multiplications in the gene for α-synuclein lead to familial parkinsonism. Interestingly, in conditions of a hereditary excess of wild-type protein, the difference in clinical severity between duplication and triplication carriers seems to suggest a direct relation to gene dosage. In the adult brain, where the protein is highly expressed, α-synuclein is thought to participate in regulating multiple crucial cellular functions related to neurotransmission. While the clinical motor symtoms of Parkinson's disease are usually attributed to a massive cell loss in the substantia nigra, we investigate how a pathogenic overabundance of wild-type α-synuclein can lead to parkinsonian symptoms as a direct result of a perturbation in its normal endogenous functions, and before an overt lesion. We show that mild overexpression of wild-type α-synuclein in the rat substantia nigra induces motor behavior attributable to disturbances in dopamine transmission, concomitant with early neurodegenerative events. Importantly, these changes are tied to the membrane association of α-synuclein, as they fail to appear upon overexpression of the binding-deficient A30P mutant. Moreover, we correlate behavioral deficits with a reduction of dopaminergic vesicles in nigrostriatal axons – showing ultrastructurally how overexpressed α-synuclein leads to deficits in neurotransmission. We demonstrate that impaired dopaminergic function can lead to Parkinson-related symtoms at an early stage of degeneration, and might indeed represent a primary step towards the demise of nigral neurons.