National Deuteration Facility

Research on the Parkinson’s disease related protein, a-synuclein, is aimed at understanding folding pathways of this protein. a-Synuclein undergoes self-association into amyloid-like fibrils through a number of not yet fully characterized oligomeric species.

In 2008-9, Agata Rekas and Seok Il Yun of the National Deuteration Facility investigated the interaction of a-synuclein with a man-made highly branched, polymer, known as “PAMAM dendrimer”. They found that the dendrimer inhibits or even reverses this abnormal self-association of a-synuclein, and thus might be a starting point in the development of better treatments for Parkinson’s disease, which affects around one in 250 Australians. With scientists at Materials Engineering, they used an electron microscope to observe the concentration-dependent effects of the dendrimer and verified the results with SANS at the NIST Center for Neutron Research, which showed a change in the shape of a-synuclein aggregates. The future research on this project aims at finding a precise localisation for PAMAM molecules on amyloid fibrils before their disaggregation occurs, and will use SANS and USANS techniques with contrast variation.

Another aspect of the involvement of a-synuclein in Parkinson’s disease is its interaction with the neurotransmitter dopamine, present in healthy neurons and depleted in Parkinson’s affected brain tissue. Based on previous research which showed that dopamine inhibits formation of a-synuclein fibrils, Agata Rekas, Robert Knott and Anna Sokolova, in collaboration with scientists at Melbourne University, used SAXS and ab-initio modelling algorithms to investigate the shape of a-synuclein oligomers formed in the presence of dopamine. This study aims at finding the mechanism of interaction of dopamine with a-synuclein and thus specifying its protective role against a-synuclein fibrillation. They found that dopamine-induced a-synuclein trimers are composed of laterally-oriented partially-overlapping protein molecules which show more defined secondary structure elements and a more consistent shape model than a-synuclein monomers. In the future, we plan to employ deuteration and neutron contrast to study these molecular interactions in more detail using QUOKKA. 

The α-synuclein monomer (left) and α-synuclein trimer (right) structures.