Toxic oligomeric alpha-synuclein variants present in human Parkinson’s disease brains are differentially generated in mammalian cell models

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Abstract

© 2015 by the authors; licensee MDPI, Basel, Switzerland. Misfolding and aggregation of α-synuclein into toxic soluble oligomeric α-synuclein aggregates has been strongly correlated with the pathogenesis of Parkinson’s disease (PD). Here, we show that two different morphologically distinct oligomeric α-synuclein aggregates are present in human post-mortem PD brain tissue and are responsible for the bulk of α-synuclein induced toxicity in brain homogenates from PD samples. Two antibody fragments that selectively bind the different oligomeric α-synuclein variants block this α-synuclein induced toxicity and are useful tools to probe how various cell models replicate the α-synuclein aggregation pattern of human PD brain. Using these reagents, we show that mammalian cell type strongly influences α-synuclein aggregation, where neuronal cells best replicate the PD brain α-synuclein aggregation profile. Overexpression of α-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 α-synuclein where the aggregates were localized in cell neurites and cell bodies.

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Xin, W., Emadi, S., Williams, S., Liu, Q., Schulz, P., He, P., … Sierks, M. R. (2015). Toxic oligomeric alpha-synuclein variants present in human Parkinson’s disease brains are differentially generated in mammalian cell models. Biomolecules, 5(3), 1634–1651. https://doi.org/10.3390/biom5031634

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