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

• Published in: Biomolecules (Basel, Switzerland) Vol. 5; no. 3; pp. 1634 - 1651
• Main Authors: Xin, Wei, Emadi, Sharareh, Williams, Stephanie, Liu, Qiang, Schulz, Philip, He, Ping, Alam, Now Bahar, Wu, Jie, Sierks, Michael R
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.07.2015; MDPI
• Subjects: aggregation; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - toxicity; Animals; Brain - pathology; Cell Differentiation - drug effects; Cell Line, Tumor; Cricetinae; Humans; Mutation; neuroblastoma cells (SH-SY5Y); Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson’s disease; Protein Multimerization; Protein Structure, Secondary; scFv antibody; α-synuclein; aggregation; scFv antibody; neuroblastoma cells (SH-SY5Y); Parkinson’s disease; α-synuclein
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom5031634

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.