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

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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 (Pountneyet 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 (Loweet 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.

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Abbreviations

AFM:

atomic force microscopy

CHAPS:

3-[(3-Cholamidopropyl) dimethyl-ammonio]-1 -propanesul-fonate

DLB:

dementia with Lewy bodies

GCI:

glial cytoplasmic inclusion

LB:

Lewy body

MSA:

multiple system atrophy

ROS:

reactive oxygen species

PD:

Parkinson’s disease

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Authors and Affiliations

  1. Department of Human Physiology, Flinders University, 5042, Bedford Park, SA, Australia

    Dean L. Pountney & Wei Ping Gai

  2. School of Chemistry, Physics and Earth Sciences weiping, Flinders University, 5042, Bedford Park, SA, Australia

    Nicolas H. Voelcker

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  1. Dean L. Pountney
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Correspondence to Wei Ping Gai.

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Pountney, D.L., Voelcker, N.H. & Gai, W.P. Annular alpha-synuclein oligomers are potentially toxic agents in alpha-synucleinopathy. Hypothesis. neurotox res 7, 59–67 (2005). https://doi.org/10.1007/BF03033776

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