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

Although a causative role of alpha-synuclein (alpha-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human alpha-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human alpha-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human alpha-syn fibrils to trigger Lewy-like alpha-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human alpha-syn. This synucleinopathy was fully developed already 10 days after fibril injection, accompanied by progressive degeneration of dopaminergic neurons in SN, neuritic swelling, reduced striatal DA release, and impaired motor behavior. Moreover, a prominent inflammatory response involving both activation of resident microglia and infiltration of CD4(+) and CD8(+) T lymphocytes was observed. Hypertrophicmicroglia were found to enclose or engulf cells and processes containing Lewy-like alpha-syn aggregates. alpha-Syn aggregates were also observed inside these cells, suggesting transfer of phosphorylated alpha-syn from the affected nigral neurons. The nigral pathology triggered by fibrils in combination with AAV-mediated overexpression of alpha-syn reproduced many of the cardinal features of the human disease. The short time span and the distinct sequence of pathological and degenerative changes make this combined approach attractive as an experimentalmodel for the assessment of neuroprotective and disease-modifying strategies.