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Calcium(II) selectively induces -synuclein annular oligomers via interaction with the C-terminal domain

¹ School of Chemistry, Physics and Earth Sciences and ² Department of Human Physiology, Flinders University, Bedford Park, SA 5042, Australia
³ Institute of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus, Denmark

(RECEIVED May 25, 2004; FINAL REVISION July 28, 2004; ACCEPTED August 5, 2004)

-Synuclein filaments are the major component of intracytoplasmic inclusion bodies characteristic of Parkinson’s disease and related disorders. The process of -synuclein filament formation proceeds via intermediate or protofibrillar species, each of which may be cytotoxic. Because high levels of calcium(II) and other metal ions may play a role in disease pathogenesis, we investigated the influence of calcium and other metals on -synuclein speciation. Here we report that calcium(II) and cobalt(II) selectively induce the rapid formation of discrete annular -synuclein oligomeric species. We used atomic force microscopy to monitor the aggregation state of -synuclein after 1 d at 4°C in the presence of a range of metal ions compared with the filament formation pathway in the absence of metal ions. Three classes of effect were observed with different groups of metal ions: (1) Copper(II), iron(III), and nickel(II) yielded 0.8–4 nm spherical particles, similar to -synuclein incubated without metal ions; (2) magnesium(II), cadmium(II), and zinc(II) gave larger, 5–8 nm spherical oligomers; and, (3) cobalt(II) and calcium(II) gave frequent annular oligomers, 70–90 nm in diameter with calcium(II) and 22–30 nm in diameter with cobalt(II). In the absence of metal ions, annular oligomers ranging 45–90 nm in diameter were observed after 10 d incubation, short branched structures appeared after a further 3 wk and extended filaments after 2–3 mo. Previous studies have shown that -synuclein calcium binding is mediated by the acidic C terminus. We found that truncated -synuclein (1–125), lacking the C-terminal 15 amino acids, did not form annular oligomers upon calcium addition, indicating the involvement of the calcium-binding domain.

Keywords: Parkinson’s disease; -synuclein; amyloid; calcium; fibrillogenesis; atomic force microscopy; Lewy body

Abbreviations: PD, Parkinson’s disease • DLB, dementia with Lewy bodies • MSA, multiple system atrophy • AFM, atomic force microscopy • MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04879704.

Reprint requests to: Nicolas H. Voelcker, School of Chemistry, Physics and Earth Sciences, Flinders University, Bedford Park SA 5042, Australia; e-mail: nico.voelcker{at}flinders.edu.au; fax: +61-8-8201-2905.

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