Annular alpha-synuclein oligomers are potentially toxic agents in alpha-synucleinopathy. Hypothesis

Dean L. Pountney, Nicolas H. Voelcker, Wei Ping Gai

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Abstract

Recently, we demonstrated that soluble 30-50 nm-sized nnular α-synuclein oligomers are released by mild detergent treatment from glial cytoplasmic inclusions (GCIs) purified from multiple system atrophy brain tissue (Pountney et al., J. Neurochem. 90:502, 2004). Dynamic antibody recognition imaging using a specific anti-α-synuclein antibody confirmed that the annular structures were positive for α-synuclein. This showed that pathological α-synucleinopathy aggregates can be a source of annular α-synuclein species. In contrast to pathological α-synuclein, recombinant α-synuclein yielded only spherical oligomers after detergent treatment, indicating a greater propensity of the pathological protein to form stable annular oligomers. In vitro, we found that Ca2+ binding to monomeric α-synuclein, specifically amongst a range of different metal ions, induced the rapid formation of annular oligomers (Lowe et al., Protein Sci., 13:3245, 2004). Hence, α-synuclein speciation may also be influenced by the intracytoplasmic Ca2+ concentration. We also showed that annular α-synuclein oligomers can nucleate filament formation. We hypothesize that soluble α-synuclein annular oligomers may be cytotoxic species, either by interacting with cell membranes or components of the ubiquitin proteasome system. The equilibrium between α-synuclein species may be influenced by intracellular Ca2+ status, interaction with lipid vesicles or other factors.

Original languageEnglish
Pages (from-to)59-67
Number of pages9
JournalNeurotoxicity Research
Volume7
Issue number1-2
DOIs
Publication statusPublished - 1 Dec 2005
Externally publishedYes

Keywords

  • α-Synuclein
  • Amyloid
  • Atomic force microscopy
  • Multiple system atrophy
  • Neurodegeneration
  • Parkinson's disease

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