Toxic Oligomeric Alpha-Synuclein Variants Present in Human Parkinson's Disease Brains Are Differentially Generated in Mammalian Cell Models.
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.
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. wie.xin@asu.edu.
Wei
W
Xin
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. sharareh.emadi@asu.edu.
Sharareh
S
Emadi
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. swilli4@asu.edu.
Stephanie
S
Williams
Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA. qiang.liu@asu.edu.
Qiang
Q
Liu
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. Philip.Schulz@asu.edu.
Philip
P
Schulz
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. pinghe2@asu.edu.
Ping
P
He
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. nalam1@asu.edu.
Now Bahar
NB
Alam
Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA. jie.wu@DignityHealth.org.
Jie
J
Wu
Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. sierks@asu.edu.
Michael R
MR
Sierks
D000818:Animals; D001921:Brain / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006224:Cricetinae; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics* / Q000633:toxicity
D051844:alpha-Synuclein
Parkinson’s disease; aggregation; neuroblastoma cells (SH-SY5Y); scFv antibody; α-synuclein