Toxic oligomeric alpha-synuclein variants present in human Parkinson’s disease brains are differentially generated in mammalian cell models

Wei Xin, Sharareh Emadi, Stephanie Williams, Qiang Liu, Philip Schulz, Ping He, Now Bahar Alam, Jie Wu, Michael Sierks

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1634-1651
Number of pages18
JournalBiomolecules
Volume5
Issue number3
DOIs
StatePublished - Jul 22 2015

Fingerprint

Synucleins
alpha-Synuclein
Poisons
Parkinson Disease
Brain
Cells
Agglomeration
Toxicity
Cell Aggregation
Immunoglobulin Fragments
Neurites
Cholinergic Agents
Cell Differentiation

Keywords

  • Aggregation
  • Neuroblastoma cells (SH-SY5Y)
  • Parkinson’s disease
  • scFv antibody
  • α-synuclein

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry
  • Molecular Biology

Cite this

Toxic oligomeric alpha-synuclein variants present in human Parkinson’s disease brains are differentially generated in mammalian cell models. / Xin, Wei; Emadi, Sharareh; Williams, Stephanie; Liu, Qiang; Schulz, Philip; He, Ping; Alam, Now Bahar; Wu, Jie; Sierks, Michael.

In: Biomolecules, Vol. 5, No. 3, 22.07.2015, p. 1634-1651.

Research output: Contribution to journalArticle

Xin, Wei ; Emadi, Sharareh ; Williams, Stephanie ; Liu, Qiang ; Schulz, Philip ; He, Ping ; Alam, Now Bahar ; Wu, Jie ; Sierks, Michael. / Toxic oligomeric alpha-synuclein variants present in human Parkinson’s disease brains are differentially generated in mammalian cell models. In: Biomolecules. 2015 ; Vol. 5, No. 3. pp. 1634-1651.
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