Tuesday, 14 April 2020 15:35

Prion transmission is an evolutionary conserved mechanism

Prions (stained in green) promote the formation of intracellular amyloid aggregates in target cells Prions (stained in green) promote the formation of intracellular amyloid aggregates in target cells Aida Revilla, CNB-CSIC
  • The use of Synthetic Biology techniques allows a better understanding of prion toxicity and transmission mechanisms
  • This new research study indicates that bacterial prions have the potential to be transmitted in  human and mice cell lines

In most cases, cellular proteins need to acquire a specific three-dimensional (3D) structure to work properly. In mammals, there are severe pathologies that are associated with an incorrect 3D protein structure, termed amyloid, with changes that affect their functionality, and diseases caused by prions belong to this group. Prions are proteins that, in their normal conformation, have a non-damaging function for the cell. However, some switches in their folding structure give them the ability to transmit this misfolded shape onto normal variants of the same protein, aggregating into fibers that can also be transmitted between cells. Initially associated with Creutzfeldt-Jacob disease in humans or spongiform encephalopathy in cattle, now proteins involved in other neurodegenrative diseases, such as Alzheimer’s, Parkinson’s,  and ELA, are also considered to be prions.
But this characteristic aggregation of prions does not occur only in mammals. In bacteria it has been shown that some proteins have this ability too, forming protein aggregates that are transmitted during cell division, and some studies suggest that, at least in vitro, they can be transmitted to other organisms.

In order to gain insight of the mechanisms behind these events, Rafael Giraldo's laboratory at the National Center for Biotechnology (CNB-CSIC), have developed a model to study the dynamics and transmission mechanisms of prions. Using synthetic biology techniques and the bacterial protein RepA–WH1, they had modified the conformational dynamics of the protein using various types of ligands such as DNA, phospholipids, or nanoparticles to induce its assembly into amyloid fibers. This model allows the study of protein toxicity in Escherichia coli, in which the original protein is harmless. The synthetic prion spreads in the form of two different structural variants during cell division. The most cytotoxic lineage produces pores in the bacterial inner membrane making it unable to detoxify free radicals that are generated as a result of membrane damage, resulting in bacterial death.

The journal mBio has just published their new work, where they have studied the transmission of the bacterial synthetic prion RepA-WH1 in cultured human and mice cell lines. Using several approaches, they have shown that prion propagation is only possible if the target cells previously contain the RepA-WH1 protein itself. In this case, the amyloid aggregates get inside the receptor cells, where they reproduce the structure on the soluble RepA-WH1 molecules, causing the formation of new intracellular amyloid aggregates. Giraldo highlights “the aggregated protein especially affects the functionality of mitochondria, the organelles responsible for cellular respiration, following an analogous mechanisms to those we had previously described in E. coli. This suggests that the mechanisms of transmission and amyloid cytotoxicity are universal and can be reconstructed by Synthetic Biology”. In addition, Giraldo remarks that one of the advantages of working with this synthetic prion is its biosecurity, since it does not spread in human or animal cells that do not naturally express RepA-WH1, allowing to understand their transmission dynamics without risks.

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