Toxic Oligomeric Alpha-Synuclein Variants Present in Human Parkinson's Disease Brains Are Differentially Generated in Mammalian Cell Models

Misfolding and aggregation of -synuclein into toxic soluble oligomeric -synuclein aggregates has been strongly correlated with the pathogenesis of Parkinson's disease (PD). Here, we show that two different morphologically distinct oligomeric -synuclein aggregates are present in human post-mortem PD brain tissue and are responsible for the bulk of -synuclein induced toxicity in brain homogenates from PD samples. Two antibody fragments that selectively bind the different oligomeric -synuclein variants block this -synuclein induced toxicity and are useful tools to probe how various cell models replicate the -synuclein aggregation pattern of human PD brain. Using these reagents, we show that mammalian cell type strongly influences -synuclein aggregation, where neuronal cells best replicate the PD brain -synuclein aggregation profile. Overexpression of -synuclein in the different cell lines increased protein aggregation but did not alter the morphology of the oligomeric aggregates generated. Differentiation of the neuronal cells into a cholinergic-like or dopaminergic-like phenotype increased the levels of oligomeric -synuclein where the aggregates were localized in cell neurites and cell bodies.