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

Protein Sci. 2004 Dec;13(12):3245-52. doi: 10.1110/ps.04879704. Epub 2004 Nov 10.


Alpha-synuclein filaments are the major component of intracytoplasmic inclusion bodies characteristic of Parkinson's disease and related disorders. The process of alpha-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 alpha-synuclein speciation. Here we report that calcium(II) and cobalt(II) selectively induce the rapid formation of discrete annular alpha-synuclein oligomeric species. We used atomic force microscopy to monitor the aggregation state of alpha-synuclein after 1 d at 4 degrees 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 alpha-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 alpha-synuclein calcium binding is mediated by the acidic C terminus. We found that truncated alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadmium / pharmacology
  • Calcium / pharmacology*
  • Cobalt / pharmacology
  • Humans
  • Magnesium / pharmacology
  • Microscopy, Atomic Force
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / ultrastructure*
  • Peptide Fragments / chemistry
  • Protein Structure, Tertiary
  • Synucleins
  • Time Factors
  • Zinc / pharmacology
  • alpha-Synuclein


  • Nerve Tissue Proteins
  • Peptide Fragments
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • Cadmium
  • Cobalt
  • Magnesium
  • Zinc
  • Calcium