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Neurotox Res. 2005;7(1-2):59-67.

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

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  • 1Department of Human Physiology and School of Chemistry, Physics and Earth Sciences, Flinders University, Bedford Park SA 5042, Australia.

Abstract

Recently, we demonstrated that soluble 30-50 nm-sized annular alpha-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-alpha-synuclein antibody confirmed that the annular structures were positive for alpha-synuclein. This showed that pathological alpha-synucleinopathy aggregates can be a source of annular alpha-synuclein species. In contrast to pathological alpha-synuclein, recombinant alpha-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 alpha-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, alpha-synuclein speciation may also be influenced by the intracytoplasmic Ca2+ concentration. We also showed that annular alpha-synuclein oligomers can nucleate filament formation. We hypothesize that soluble alpha-synuclein annular oligomers may be cytotoxic species, either by interacting with cell membranes or components of the ubiquitin proteasome system. The equilibrium between alpha-synuclein species may be influenced by intracellular Ca2+ status, interaction with lipid vesicles or other factors.

PMID:
15639798
[PubMed - indexed for MEDLINE]
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