Professor Daniel Otzen
Interdisciplinary Nanoscience Research Center (iNANO), Aarhus University
Wednesday 5th November, 4.00 p.m., Stacey Lecture Theatre 1
The 140-residue protein alpha-synuclein (aSN) is a key player in the development of Parkinson’s Disease, characterized by the death of i.a. dopaminergic neurons. Although natively unfolded as a monomer in solution, aSN readily forms amyloid fibrils which accumulate as intracellular inclusions. It is however increasingly accepted that the cytotoxic species are smaller oligomeric (non-fibrillar) states, which can disrupt phospholipid vesicles in vitro. The role of the oligomer in the aggregation of aSN is unclear. We have recently demonstrated that aSN can form oligomers of at least two different size classes. The smaller oligomer has a mean size of 430 ± 88 kDa or 30±6 aSN monomers. It consists of a dense core and a more extended or unfolded shell which is unable to elongate fibrils, but rather inhibits amyloid formation in a concentration-dependent way, consistent with an off-pathway oligomer [1]. Hydrogen-deuterium exchange mass spectrometry reveals that this oligomer in fact consists of two co-existing oligomer populations with different hydrogen-bond protection patterns. The majority species (75-80%) is only protected in the central part of the sequence and is not in exchange with monomers, while the minority species is more protected but likely exchanges through the monomer. We suggest that the minority species is on-pathway and can form fibrils by incorporating monomers, while the majority species is the cytotoxic off-pathway species [2]. Cytotoxic membrane permeabilization is inhibited by the plant compound EGCG (epigallocatechin gallate) by a mechanism that is rather unexpected: there are no changes in overall oligomer structure or size but the C-terminal tail, which is otherwise mobile, becomes relatively immobilized and the affinity for membranes is highly diminished [3].
References:
1.Lorenzen, N. et al. & Otzen, D. E. (2014). The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation. J. Am. Chem. Soc. 136, 3859-68.
2.Paslawski, W. et al. & Otzen, D. E. (2014). Co-existence of two different α-synuclein oligomers with different core structures determined by Hydrogen/Deuterium Exchange Mass Spectrometry. Angew Chem Int Ed Engl Apr 16 (Hot Paper), [Epub ahead of print].
3.Lorenzen, N. et al. & Otzen, D. E. (2014). How epigallogatechin gallate can inhibit α-synuclein oligomer toxicity in vitro. J. Biol. Chem. In press (Paper of the Week).