Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson’s disease

Parkinson's disease is characterized by a progressive accumulation of alpha-Synuclein (alpha Syn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of alpha Syn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of alpha Syn, we developed a novel mouse model with enhanced alpha Syn secretion and cell-to-cell transmission. Expression of the secreted alpha Syn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted alpha Syn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released alpha Syn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted alpha Syn is cell-to-cell transmitted. The secreted alpha Syn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson's disease-like phenotype that includes a robust alpha Syn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson's disease. In summary, a novel animal model of Parkinson's disease based on enhanced cell-to-cell transmission of alpha Syn was developed. The neuron-produced cell-to-cell transmitted alpha Syn triggers all phenotypic features of experimental Parkinson's disease in mice.