Toxic Oligomeric Alpha-Synuclein Variants Present in Human Parkinson's Disease Brains Are Differentially Generated in Mammalian Cell Models.
| Autor: | Xin W; Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. wie.xin@asu.edu., Emadi S; Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. sharareh.emadi@asu.edu., Williams S; Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. swilli4@asu.edu., Liu Q; Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA. qiang.liu@asu.edu., Schulz P; Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. Philip.Schulz@asu.edu., He P; Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. pinghe2@asu.edu., Alam NB; Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. nalam1@asu.edu., Wu J; Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA. jie.wu@DignityHealth.org., Sierks MR; Chemical Engineering, Arizona State University, Tempe, AZ 85287-6106, USA. sierks@asu.edu. |
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| Jazyk: | angličtina |
| Zdroj: | Biomolecules [Biomolecules] 2015 Jul 22; Vol. 5 (3), pp. 1634-51. Date of Electronic Publication: 2015 Jul 22. |
| DOI: | 10.3390/biom5031634 |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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