Predominant neuritic pathology induced by viral overexpression of alpha-synuclein in cell culture

1. Alpha-synuclein is known to play an important role in the pathogenesis of Parkinson's disease (PD). The pathogenicity of alpha-synuclein is related to its ability to form intraneuronal inclusions. The inclusions, which are found in brains of patients with PD and diffuse Lewy body disease consist partially of C-terminally truncated alpha-synuclein. This alpha-synuclein species has an increased ability to form aggregates compared to full length alpha-synuclein.2. We have used an adeno-associated virus (AAV) vector system to overexpress either C-terminally truncated or full length alpha-synuclein containing the A53T mutation, which have both been identified in brains of familial PD patients and transgenic mouse models. Dissociated mesencephalic neurons, cerebellar granule neurons, and organotypic midbrain slice cultures were infected with AAV containing the transgene under the control of the cytomegalovirus promoter.3. We demonstrate that viral overexpression of alpha-synuclein(A53T) leads to the formation of distorted neurites, intraneuritic swellings, and granular perikaryal deposits in cultured neurons. Our results indicate that these cell culture models may represent an early phase of PD reflecting pathologic neuritic alterations before significant neuronal cell loss occurs.