Neurotoxicity Research

, Volume 7, Issue 1, pp 59–67

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

  • Dean L. Pountney
  • Nicolas H. Voelcker
  • Wei Ping Gai
Article

DOI: 10.1007/BF03033776

Cite this article as:
Pountney, D.L., Voelcker, N.H. & Gai, W.P. neurotox res (2005) 7: 59. doi:10.1007/BF03033776

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.

Keywords

α-SynucleinParkinson’s diseaseAmyloidMultiple system atrophyAtomic force microscopyNeurodegeneration

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

Copyright information

© Springer 2005

Authors and Affiliations

  • Dean L. Pountney
    • 1
  • Nicolas H. Voelcker
    • 2
  • Wei Ping Gai
    • 1
  1. 1.Department of Human PhysiologyFlinders UniversityBedford ParkAustralia
  2. 2.School of Chemistry, Physics and Earth Sciences weipingFlinders UniversityBedford ParkAustralia