Transmission of Soluble and Insoluble &agr;-Synuclein to Mice

Abstract The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, &agr;-synuclein (&agr;-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous &agr;-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic &agr;-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of &agr;-syn. These results provide further insight into the prion-like mechanisms of &agr;-syn and suggest that disease-associated &agr;-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.