1 Interdisciplinary Nanoscience Center - INANO-MBG, iNANO-huset, Interdisciplinary Nanoscience Center, Science and Technology, Aarhus University2 Department of Genetics and Biotechnology, Faculty of Agricultural Sciences, Aarhus University, Aarhus University3 Department of Molecular Biology and Genetics - Protein science, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University4 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark5 Interdisciplinary Nanoscience Center - INANO-MBG, iNANO-huset, Interdisciplinary Nanoscience Center, Science and Technology, Aarhus University
Neurodegenerative disorders are characterized by the formation of protein oligomers and amyloid fibrils, which in the case of Parkinson's disease involves the protein α-synuclein (αSN). Cytotoxicity is mainly associated with the oligomeric species, but we still know little about their assembly and structure. Hydrogen/deuterium exchange (HDX) monitored by mass spectrometry is used to analyze oligomers formed by wild-type (wt) αSN and also three familial αSN mutants (A30P, E46K, and A53T). All four variants show co-existence of two different oligomers. The backbone amides of oligomer type I are protected from exchange with D2 O until they dissociate into monomeric αSN by EX1 exchange kinetics. Fewer residues are protected against exchange in oligomer type II, but this type does not revert to αSN monomers. Both oligomers are protected in the core sequence Y39-A89. Based on incubation studies, oligomer type I appears to form straight fibrils, while oligomer type II forms amorphous clusters that do not directly contribute to the fibrillation process.
Angewandte Chemie (international Edition), 2014, Vol 53, Issue 29, p. 7560-7563