Programme Contents

Shedding light on neurodegeneration: small angle X-ray scattering and misfolded proteins

The misfolding pathways that lead to cytotoxic species vary between diseases such as Alzheimer’s (AD), Huntington’s and Parkinson’s but there is a common link in that they all involve some form of oligomeric species, in contrast to the extra- or intra-cellular fibrillar deposits of aggregated protein that are regarded as end products of the pathological process (Villemagne et al., 2010). To elucidate possible folding pathways for the amyloid β peptide of AD (Aβ) we made time-resolved, stopped-flow SAXS measurements at the Australian Synchrotron on Aβ 1-40 and Aβ 1-42 peptides in dilute NaOH (13mM) that were rapidly mixed with pH 6.9 phosphate buffered saline containing Cu²⁺ ions. These showed that protofibril formation occurred in less than one second in either control or Cu²⁺–containing buffer and that evolution of the fibrils in subsequent seconds followed a non-linear pattern. Static measurements on the peptides that had been reacted with sub-micellar concentrations of the lipid mimetic, N-lauroylaminopropyl-N′,N′- dimethylamine oxide (LDAO) and a dipeptide formed of tyrosine 10 cross-linked Aβ 1-40 (Kok et al., 2009), however, gave a stable well-defined “Y” shaped structure for both the di-tyrosine linked peptide and LDAO- associated Aβ 1-42. The “Y” shape is reminiscent of the Fc antibody fragment. Since the di-tyrosine linked peptide is neurotoxic, as in the case of cytotoxic antibodies, its two arms may carry ligands able to cross-link cell membrane receptors to initiate a cytotoxic cascade.

Villemagne VL, Perez KA, Pike KE, Kok WM, Rowe CC, White AR, Bourgeat P, Salvado O, Bedo J, Hutton CA, Faux NG, Masters CL, Barnham KJ (2010) Journal of Neuroscience 30: 6315-22.

Kok WM, Scanlon DB, Karas JA, Miles LA, Tew DJ, Parker MW, Barnham KJ,Hutton CA (2009) Chemical Communications (Cambridge, England) 7: 6228-30.