Neuroscience in Denmark


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General information

Name (center, department, group or other)
Protein biophysics group, iNANO, Aarhus University
Contact name
Daniel Otzen
Contact email
dao#at#inano#dot#au#dot#dk
Contact title
Professor
Date
26. June 2015
(Last edited: 1. March 2017)

Brief description of research activities

We work with protein conformational changes in general. One of our major research areas is protein aggregation, including the aggregation of the protein alpha-synuclein involved in Parkinson's Disease. We analyze how the cytotoxic oligomers form in vitro, bind to membrane vesicles and interact with cellular components in vivo. We also analyze how small molecules may inhibit or promote alpha-synuclein aggregation, and the molecular mechanisms governing these processes.
In addition, we analyze aggregation of the protein TGFBIp involved in corneal dystrophies as well as the benign formation of amyloid in bacteria. Functional amyloid makes important contributions to the formation and strength of bacterial biofilm and we are currently trying to elucidate the mechanisms involved in the controlled build-up of highly stable amyloid structures.
Finally, we have increasing focus on the amyloid produced naturally by bacteria (functional amyloid) and their possible relationship to the induction of pathological protein aggregation in humans, e.g. via the gut-brain axis linking microbiomic amyloid with the brain.

Keywords

alpha-synuclein, Parkinson's Disease, oligomer, membrane binding, biophysical approaches, corneal dystrophies, TGFBIp, functional amyloid, biofilm.

Research tools and techniques

Our own expertise is based on spectroscopic methods such as fluorescence, circular dichroism, light scattering and FTIR as well as calorimetry, AFM and confocal laser scanning microscopy. We have several plate readers for relatively high-throughput analysis of protein aggregation behaviour. Much of our work is carried out in collaboration with partners providing cutting-edge expertise in Small-Angle X-ray Scattering, Hydrogen-Deuterium Exchange Mass Spectrometry and NMR.

Scientific Personnel

No of Associate Professors/Postdocs: 2
No of PhD students: 9
Other: 1

Key references from within the last 5 years

1. Tian, P., Boomsma, W., Wang, Y., Otzen, D. E., Jensen, M. H., and Lindorff-Larsen, K. (2015) Structure of a Functional Amyloid Protein Subunit Computed Using Sequence Variation, J. Am. Chem. Soc. 137, 22-25.
2. Paslawski, W. et al and Otzen, D. E. (2015) Cooperative folding of a polytopic α-helical membrane protein involves a compact N-terminal nucleus and non-native loops, Proc. Natl. Acad. Sci. USA In press.
3. Otzen, D. (2015) Protein aggregation: Close encounters of the greasy kind, Nature Chem. Biol. 11, 176–177.
4. Paslawski, W. et al and Otzen, D. E. (2014) Co-existence of two different α-synuclein oligomers with different core structures determined by H/D Exchange Mass Spectrometry, Angew Chem Int Ed Engl 53, 7560-7563.
5. Paslawski, W. et al and Otzen, D. E. (2014) High stability and cooperative unfolding of cytotoxic α-synuclein oligomers Biochemistry 53, 6252-6263.
6. Lorenzen, N. et al. and Otzen, D. E. (2014) How epigallogatechin gallate can inhibit α-synuclein oligomer toxicity in vitro, J. Biol. Chem. 289, 21299-21310.
7. Lorenzen, N., Nielsen, S. B., Buell, A. K., Kaspersen, J. D., Arosio, P., Vad, B. S., Paslawski, W., Christiansen, G., Valnickova-Hansen, Z., Andreasen, M., Enghild, J. J., Pedersen, J. S., Dobson, C. M., Knowles, T. J., and Otzen, D. E. (2014) The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation, J. Am. Chem. Soc. 136, 3859-3868.
8. Otzen, D. E., (Ed.) (2012) Amyloid Fibrils and Prefibrillar Aggregates Wiley-VCH Verlag GmbH.
9. Andreasen, M., Nielsen, S. B., Runager, K., Christiansen, G., Nielsen, N. C., Enghild, J. J., and Otzen, D. E. (2012) Polymorphic fibrillation of the destabilized fourth fasciclin-1 domain mutant A546T of the transforming growth factor-beta-induced protein (TGFBIp) occurs through different pathways with different oligomeric intermediates, J. Biol. Chem. 287, 34730-34742.
10. Giehm, L., Svergun, D. I., Otzen, D. E., and Vestergaard, B. (2011) Low resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation, Proc. Natl. Acad. Sci. U.S.A. 108, 3246-3251.

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