In vivo demonstration that α-synuclein oligomers are toxic

The aggregation of proteins into oligomers and amyloid fibrils is characteristic of several neurodegenerative diseases, including Parkinson disease (PD). In PD, the process of aggregation of alpha-synuclein (alpha-syn) from monomers, via oligomeric intermediates, into amyloid fibrils is considered the disease-causative toxic mechanism. We developed alpha-syn mutants that promote oligomer or fibril formation and tested the toxicity of these mutants by using a rat lentivirus system to investigate loss of dopaminergic neurons in the substantia nigra. The most severe dopaminergic loss in the substantia nigra is observed in animals with the alpha-syn variants that form oligomers (i.e., E57K and E35K), whereas the alpha-syn variants that form fibrils very quickly are less toxic. We show that a-syn oligomers are toxic in vivo and that alpha-syn oligomers might interact with and potentially disrupt membranes.