Alpha-synuclein oligomers: structure stabilization and cytotoxic function in neurodegeneration

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Pountney, Dean
Gai, W.
Voelcker, N.
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Alpha-synuclein oligomers: structure stabilization and cytotoxic function in neurodegeneration Pountney D.L.1, Gai W.P.2 and Voelcker N.H.3 1School of Medical Science, Griffith University, Gold Coast. 2School of Medicine, Flinders University, Adelaide. 3School of Chemistry, Physics and Environmental Science, Flinders University, Adelaide. Parkinson's Disease and the Parkinson's-plus diseases are linked to the redistribution within neural cells of the protein alpha-synuclein. Microscopically visible cytoplasmic aggregates, or inclusion bodies, composed largely of alpha-synuclein filaments are a common pathological hallmark of these diseases. However, current studies indicate that inclusion body formation is part of a protective mechanism and that the formation of apparently inert protein filaments is a way of sequestering potentially cytotoxic soluble alpha-synuclein species from the cell. Purification of inclusion bodies by magnetic immunocapture has enabled detailed analysis of their molecular architecture. At the ultrastructural level, inclusion bodies are composed of 9-10 nm amyloid-like alpha-synuclein filaments. The inclusion body filaments are coated with amorphous material comprised of many proteins, including alpha-synuclein. Recombinant alpha-synuclein can also form annular macromolecular structures that are morphologically similar to bacterial pore-forming toxins. These species are able to permeabilize lipid vesicles, indicating that they may represent the cytotoxic agent in disease. Recently, we have shown that annular alpha-synuclein oligomers are released after dissociation of inclusion bodies isolated from post-mortem brain tissue. This demonstrates that pathological synucleinopathy aggregates can be a source of annular alpha-synuclein species. In addition, the occurrence of covalently cross-linked alpha-synuclein oligomers suggests that intermolecular cross-linking of protein chains due to inter-residue oxidation may promote alpha-synuclein annular oligomer stabilization. We have also shown that the addition of calcium(II) to the recombinant alpha-synuclein monomer, selectively amongst a range of different metal ions, induces annular oligomers in high yield. These findings are the first to link calcium, which is known to play a central role in synaptic vesicle trafficking and is differentially regulated in Parkinson's Disease, and annular alpha-synuclein oligomer formation. Supported by the Parkinson's Disease Foundation.

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