Prion Progenitor Degrades Into Monomers Under Hydrostatic Pressure

Prions are an altered form of protein. The complex three-dimensional structure of a prion’s progenitor protein changes, somehow causing it to no longer function as intended.

Not only that, but the malformation of these progenitor proteins into prions makes them clump into amyloid plaques that can result in a disease state. Prions are responsible for protein-caused infectious neurodegenerative diseases like Mad Cow disease and scrapie in livestock.

The protein α-synuclein (α-syn) has recently been implicated as a prion progenitor. In its normal state, the protein is found at the presynaptic terminals of neurons, from which chemical signals called neurotransmitters are released from one neuron to the next or from a neuron to an organ or other tissue type.

Prion Progenitor Protein α-synuclein


But when acting like a prion, α-syn fibrils aggregate in the neurons into irregular structures with hydrophobic cores called Lewy bodies. The latter has been implicated in the neurodegenerative motor system disorder Parkinson’s disease (PD), including the autosomal-dominant form of PD that is associated to known genetic mutations A30P, A53T and E46K.


A team led by Jerson Lima Silva at the Federal University of Rio de Janeiro, Brazil, studied the structure of pathogenic α-syn fibril plaques and how they act at an atomic scale. In their study the group shows how pressure breaks apart α-syn fibril, like those found in Lewy bodies, into monomers.


High Hydrostatic Pressure


The technique reveals all the steps in the process of protein folding and unfolding as though they were instructions for building an origami figure. Silva’s team coupled HHP with nuclear magnetic resonance (NMR) spectroscopy to obtain, for the first time, a picture of what happens on an atomic scale.




Neutralizing Fibril Propagation

By replicating the structural form of the protein found in the disease state and then reverting the protein back to its properly functioning configuration, Silva’s team hopes to aid in the development of new strategies to treat Parkinson’s disease. Specifically, the team believes the research may provide a way forward to block the formation of new α-synuclein aggregation and perhaps prevent it from even starting.

Further, the work may be used to signal the beginnings of Parkinson’s disease markers and thus be used in early diagnosis.

“HHP is a potential tool for developing a new generation of target species and for drug screening studies” says Silva.


Guilherme A. P. de Oliveira, et al
Scientific Reports 6, Article number: 37990 (2016) doi:10.1038/srep37990

Image: Dr. Wei-Feng Xue, Wellcome Images. Atomic force micrograph showing the topography of amyloid-like fibrils.