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Biomolecules 2015, 5(3), 1634-1651; doi:10.3390/biom5031634

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

1
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA
2
Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Stephan N. Witt
Received: 15 January 2015 / Revised: 17 June 2015 / Accepted: 26 June 2015 / Published: 22 July 2015
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Abstract

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. View Full-Text
Keywords: Parkinson’s disease; α-synuclein; aggregation; scFv antibody; neuroblastoma cells (SH-SY5Y) Parkinson’s disease; α-synuclein; aggregation; scFv antibody; neuroblastoma cells (SH-SY5Y)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Xin, W.; Emadi, S.; Williams, S.; Liu, Q.; Schulz, P.; He, P.; Alam, N.B.; Wu, J.; Sierks, M.R. Toxic Oligomeric Alpha-Synuclein Variants Present in Human Parkinson’s Disease Brains Are Differentially Generated in Mammalian Cell Models. Biomolecules 2015, 5, 1634-1651.

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