Speaker: Wei-Feng Xue (School of Biosciences, University of Kent, UK)
Subject: Nanoscale properties of the amyloid life-cycle
Location: TU Delft
Date: Thursday, 12.05.2016, 16:00-17:00
Author: Edgar Schönfeld
Amyloids are misfolded proteins that self-assemble into filaments (fibrils), typically 10 nm wide and several micrometers long (Fig.1). While amyloid fibrils are typically associated with a variety of diseases, there is growing evidence for functional roles in cellular processes for some kinds of amyloid fibrils. Amyloids are thought to be the cause of Alzheimer’s and Parkinson disease. The extracellular amyloid deposits are thought to be cytotoxic. Prions are transmissible amyloids, mainly being known for their role in mad-cow disease and Kreutzfeld-Jakob syndrome. However, according to Xue, the border between amyloids and prions blurs increasingly, as amyloids with prion-like properties are being found.
Xue investigates why some amyloids are transmissible, while others are not, and what makes some amyloids more cytotoxic than others. To address these questions, Xue examines the structural properties of amyloid fibrils at the mesoscopic scale (nm-µm), as the size and shape of the fibers in this spatial regime determines their function. Within the last 10 years Xue characterized amyloid fibrils in terms of nucleation- and fragmentation behavior, stability and the effects of fibril length. He was able to relate these quantities to the cytotoxicity and transmissibility of amyloid fibrils.
In fact, amyloid fibers that are a 100% identical in the atomic structure of their components can take greatly different shapes. Yet, structural properties common to all amyloid fibrils are their corkscrew-shape and the fact that they are are built up of beta-sheets running perpendicular to the fibril’s main axis. The formation of these fibers can be described by the amyloid life-cycle (Fig.2), a term that not all of Xue’s colleagues agree with.
The initial step of the lifecycle is the primary nucleation, meaning that monomers come together to form a sequence of connected components. The secondary nucleation refers to the further elongation of this basic polypeptide. The reason that this distinction is made is that primary nucleation has to overcome a large energy barrier. For this reason, it proceeds so slowly that one can say that people in their 80’s who do not have Alzheimer’s yet will never get it. If one were to measure fibril concentration in solution over time after addition of the amyloid building blocks, one can distinguish two possible outcomes: either a lag phase followed by a steep increase in fibril concentration, or an immediate increase in concentration that levels off over time. The latter observation is associated with secondary nucleation, which is associated with a lower energy barrier and therefore occurs faster.
There are studies out there claiming that Alzheimers is transmissible. In these studies, amyloid fibrils were directly transmitted from a diseased to a healthy animal. According to Xue, the reason why those animals subsequently develop Alzheimer’s is that the transmitted fibril fragments can be seen as ‘seeds’, only requiring secondary nucleation to form fibrils. The next step in the amyloid life-cycle is fragmentation. In Xue’s lab fibrils of different sizes were analyzed under the microscope. They found that cytotoxicity is mediated through the interaction of the terminal ends of the fragmented fibrils with cell membranes. Thus, the more fragmented a fibril is, the more damage it can cause to a cell. For this reason, Xue says that Alzheimer therapies aimed at dissolving amyloids may actually be counterproductive. It is, however, unclear at this point what gives the terminal ends of the fragments the ability to disrupt membranes. Xue has ambitious goals with regard to research on amyloids, and his contagious enthusiasm leaves no doubt he will be successful in doing so.
Research on amyloids will at some point benefit patients. For the case of Alzheimer’s, Xue suggests that, given his findings, preventing fragmentation of already existing fibrils could slow down further neurodegeneration.
 Xue WF. Nucleation: The Birth of a New Protein Phase. Biophys J. 2015 Nov 17;109(10):1999-2000