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. 2012 May 25;149(5):968-77.
doi: 10.1016/j.cell.2012.05.007.

Transmissible proteins: expanding the prion heresy

Claudio Soto  1
Affiliations

Transmissible proteins: expanding the prion heresy

Claudio Soto. Cell. .

Abstract

The once-heretical concept that a misfolded protein is the infectious agent responsible for prion diseases is now widely accepted. Recent exciting research has led not only to the end of the skepticism that proteins can transmit disease but also to expanding the concept that transmissible proteins might be at the root of some of the most prevalent human illnesses. At the same time, the idea that biological information can be transmitted by propagation of protein (mis)folding raises the possibility that heritable protein agents may be operating as epigenetic factors in normal biological functions and participating in evolutionary adaptation.

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Figures

Figure 1
Figure 1. Properties required for misfolded aggregates to behave as transmissible proteins
Based on the knowledge of the factors controlling prion transmission in vivo, it is likely that the following characteristics are needed for spreading of misfolded proteins: 1) Efficient replication by the seeding-nucleation process. 2) Resistance to biological clearance, which in the figure is illustrated by proteasomal degradation, chaperone re-folding and autophagy, although it is likely that other pathways might be also operating. 3) Ability to reach the target tissue and cellular location, which is represented in the figure by cellular transport and spreading, and penetration across the intestinal and blood-brain barriers. The biological barriers to be surmounted by the transmissible protein depend on the specific disease, sub-cellular location of the misfolded aggregates and routes of exposure. 4) Capability to transmit a biological change. For disease-associated misfolded proteins the change is cellular damage, tissue dysfunction and clinical disease and for functional infectious proteins, the phenotypic change is the modulation of a biological activity or acquisition of a new function. In the figure, functional changes are illustrated with the case of the Curli bacterial amyloid involved in biofilm formation (Chapman et al., 2002) and with the regulation of translational termination by Sup35 in yeasts that may be implicated in evolutionary adaptation to environmental changes (True and Lindquist, 2000).
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