Speaker: Wei-Feng Xue
Department: School of Biosciences, University of Kent
Subject: Nano-scale properties of the amyloid life-cycle
Location: TU Delft
Date: 12 May 2015
Author: Gabriele Kockelkoren
Wei-Feng Xue leads a research group at the school of Biosciences at the University of Kent. Its work focusses of the mechanisms of amyloid assembly. In his lab a multidisciplinary approach can be found, physics and biology are combined in numerous ways. With great enthusiasm and a constant smile on his face, this seminar was extremely pleasant to attend.
The lab focusses on the life-cycle of amyloid. Amyloids are fibrillary structures formed out of peptides, these are aggregates. These structures are nanometers wide and micrometers long. Amyloids have disease-associated properties. Examples of these diseases are Alzheimer, Parkinson and Diabetes. In terms of disease, amyloids are interesting for studying their formation, growth, interaction and toxicity to cells. Next to amyloids, prions exist. Prions are transmissible amyloids associated with diseases, like the Mad-Cow disease and Creutzfeldt-Jakob disease. So the main difference is their propagation and transmission. The border between amyloid and prions disease is quite blurred, that is because some diseases have the tendency to transmit themselves. Xue tries to find out what makes amyloids transmissible or not. Amyloids fibres are potential candidates for high-performance nanomaterials due to their strong mechanical strength and great elasticity. Amyloid have a beta structure sheet going perpendicular to the fibre structure and are formed out of a great variety of proteins.
Figure 1: AFM image of amyloid filaments. Source: https://nanotechlab.physik.unibas.ch/NSLBildergallerie.html
Biophysics behind amyloid formation is extremely complex. Amyloids are known in a great variety of species. All amyloid species have a resembling free energy diagram in formation. To be able to fold the ‘pre-amyloids’ have to cross a free energy barrier. This suggests that their formation is extremely slow. Of-course from a disease point of view this is very favourable, as it takes a long time to get the disease.
In the lab they find conditions to get up this amyloid-formation kinetics to form them more fast. When monomers are put together in solution, it takes a long time before nucleation starts. This waiting time is called the lag phase. The lag phase is followed by an exponential growth until a plateau is reached, this is the case for amyloids. In the case of prions the lag time is skipped because preformed polymers are trans missed. After this first nucleation step, seeding succeeds. Seeding is the process were polymers that have been formed fragment. New polymers form out of the fragmented pieces. The real interesting question is why some amyloid are not really transmissible. In living systems there are a lot of ways to go into amyloid formation. They are formed out of oligomers that proliferate through secondary pathways.
Figure2: The amyloid life cycle. An amyloid is depicted as a circle, the soluble monomeric protein as parallelograms. The main processes in amyloid assembly are given by the red arrows, primary nucleation by the purple arrow and secondary nucleation by the blue and orange arrow. Source: Wei-Feng Xue, Nucleation: The Birth of a New Protein Phase, Biophysical Journal, Volume 109, Issue 10, 17 November 2015, Pages 1999-2000, ISSN 0006-3495, http://dx.doi.org/10.1016/j.bpj.2015.10.011.
Xue tends to talk about the life-cycle of amyloid assembly. He sees it as a circular process with a positive feedback-loop. From primary nucleation (de novo), there are secondary pathways (fragmentation and secondary nucleation). This forms new entities and seeds of amyloids. According to Xue, it resembles population dynamics.
His lab is interested in the structure of fibres, however not at atomic level. They have found that the fibril size and shape defines their biological activities, even though at atomic level they may seem fairly similar. Actually, size and shape gives a wide variety of responses. The amyloid fibrils are highly stable and can resist to chemicals, high concentrations of detergents and high temperatures. In the lab they look at how they interact with vessels and are interested are size distribution, persistence length, force resistance. AFM is used as a structural tool at mesoscopic length scale to look at how fibres twist and behave.
I enjoyed this talk very much and it was really nice for Nanobiology students. Kent is an enthusiastic speaker who inspires scientists around the world.