Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain

Significance Parkinson’s disease is the most common neurodegenerative movement disorder, but its faithful modeling in animals has been challenging. Animal models based on overexpression of the disease-causing protein, α-synuclein (α-syn), are useful for studies of disease pathogenesis but rely on unphysiologically high levels of α-syn. Here, we present a model that combines preformed human α-syn fibrils and adenoassociated virus (AAV)-mediated overexpression of human α-syn, given in doses that, by themselves, do not cause any acute neurodegeneration. This combined approach reproduces several cardinal features of the human disease, including Lewy-like synucleinopathy, neuroinflammation, and progressive dopaminergic cell loss. The short time span and distinct sequence of pathological and degenerative changes make it attractive as an experimental model for studies aimed at neuroprotection and disease modification.