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

Biomolecules

Wei Xin¹  Sharareh Emadi¹  Stephanie Williams¹  Qiang Liu²  Philip Schulz¹  Ping He¹  Now Bahar Alam¹  Jie Wu²  Michael R. Sierks¹ 

[1] Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA; E-Mails:;Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA; E-Mails:

关键词: Parkinson’s disease;    α-synuclein;    aggregation;    scFv antibody;    neuroblastoma cells (SH-SY5Y);   

DOI  :  10.3390/biom5031634

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.