Nano-scaled properties of the amyloid life-cycle

Speaker: Wei-Feng Xue

Department: School of Biosciences, University of Kent

Subject: Nano-scaled properties of the amyloid life-cycle

Location: TU Delft

Date: 12-05-16

Author: Hielke Walinga

When people first discovered the cause of the mad-cow disease, they thought it was some kind of black magic in nature. It was caused by a misfolded protein that could convert other proteins into a misfolded protein as well. They called them prions. These proteins were insoluble and aggregated after their replication. It was a kind of life that was even stranger than viruses, something that was already discussed as something that cannot be classified as life anymore. Now, it becomes clear that other diseases might as well be prion linked diseases, like Alzheimer, Parkinson, and Diabetes type II. Researching the properties of these proteins, and its non-toxic variant the amyloid, becomes therefore more and more important.

The presenter of this talk is Wei-Feng Xue and he researched the nano-scale properties of the amyloid life-cycle. Xue explained that amyloids could be a potential nanomaterial because of its mechanical strength and elasticity, but in his presentation he primarily focusses on the disease linked properties of the amyloids, or the prions.

Amyloids are just fibers (in fact they are stalked cross beta sheets) and the list of functional amyloids in organisms grows and grows. If we could know more about its general life-cycle we might discover what makes some amyloids become the toxic prion variant. The prion is in fact just a transmissible amyloid (you can get infected for example by eating infected food). Our focus on prions should therefore be directed to its propagation and transmission.

The life-cycle of amyloids can be divided in three parts. First there is the nucleation; this is the forming of the first amyloids. When the amyloids are formed, they will grow by recruiting more proteins on them. This is the elongation. Then there is the fragmentation; this is the dividing of the amyloids in multiple pieces. This process goes largely together with elongation. What’s more, Xue believes that in the beginning there is a period of largely elongation, and after that there is a large period which is dominated by fragmentation. After that, steady state should be achieved, but, this is just a prediction.

Nucleation is a rather slow process. There is large energy barrier that needs to be crossed and this just takes a long time. That’s also the reason why Alzheimer, Parkinson, and Diabetes type II are largely found by older people. Other infectious prion diseases might originally have arisen by spontaneous nucleation, but when spread they will be seeded. Like for example when you eat infected food. In the lab, nucleation is sped up by increasing the concentration or by a special solution.

The length of the amyloid largely reflects the properties of it. Longer fibers are much more stable, although in live you will find decreasing lengths. In the disease’s perspective, fragmentation is good; because it increases net growth and increases the toxicity (short fibrils disrupt the membrane). It should be interested how this fragmentation really works, and how the chaperones of the cell react on these amyloids.

I think this research gives great new insights in diseases and might reveal more diseases which are caused by amyloids or which symptoms can be explained by amyloids. In a project for my Bachelor I found for example that Huntington disease patients certain proteins that are linked to prions have an increased concentration. This might explain certain symptoms of the disease.

amyloid_lifetimeImage 1: The predicted life-cycle of an amyloid. The average length vs. the time; log-log scale. Blue is dominated by elongation, red is dominated by fragmentation, green is the steady state. (Source: Xue, Wei-Feng, and Sheena E. Radford. “An imaging and systems modeling approach to fibril breakage enables prediction of amyloid behavior.” Biophysical journal 105.12 (2013): 2811-2819.)

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