Misfolding and aggregation of Î±-synuclein into toxic soluble oligomeric Î±-synuclein aggregates has been strongly correlated with the pathogenesis of Parkinsonâ€™s disease (PD). Here, we show that two different morphologically distinct oligomeric Î±-synuclein aggregates are present in human post-mortem PD brain tissue and are responsible for the bulk of Î±-synuclein induced toxicity in brain homogenates from PD samples. Two antibody fragments that selectively bind the different oligomeric Î±-synuclein variants block this Î±-synuclein induced toxicity and are useful tools to probe how various cell models replicate the Î±-synuclein aggregation pattern of human PD brain. Using these reagents, we show that mammalian cell type strongly influences Î±-synuclein aggregation, where neuronal cells best replicate the PD brain Î±-synuclein aggregation profile. Overexpression of Î±-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 Î±-synuclein where the aggregates were localized in cell neurites and cell bodies.
Digital Object Identifier (DOI)
Xin, Wei; Emadi, Sharareh; Williams, Stephanie; Liu, Qiang; Schulz, Philip; He, Ping; Alam, Now Bahar; Wu, Jie; and Sierks, Michael R., "Toxic Oligomeric Alpha-Synuclein Variants Present In Human Parkinsonâ€™S Disease Brains Are Differentially Generated In Mammalian Cell Models" (2015). Translational Neuroscience. 175.