How, exactly, do prion proteins cause disease?

Prion Protein Fibrils via NIAID When prions were first discovered in the 1980s it was immensely controversial whether an isolated protein molecule could act as an infectious agent without any associated nucleic acid, that is, without a genome to encode future generations. I was lucky enough to be able to follow from the sidelines as the prion story slowly unfolded throughout the 1990s. By and large, most of the major questions about prions seem now to have been answered, but one big issue still remains – how exactly do these proteins cause disease?

In contrast to the normally-folded cellular form of the prion protein found in “uninfected” cells, the misfolded disease-causing version of the protein is toxic to brain cells. In a new paper in Nature, Adriano Aguzzi’s group suggests that the prion protein contains a “switch” that controls its toxicity. This switch covers a tiny area on the surface of the protein. If another molecule, for example an antibody, touches this switch, a lethal mechanism is triggered that can lead to very fast cell death (The flexible tail of the prion protein mediates the toxicity of antiprion antibodies. Nature, 31 July 2013 doi: 10.1038/nature12402 - sorry, subscription).

The prion protein consists of two functionally distinct parts: a globular domain, which is tethered to the cell membrane, and a long and unstructured tail. Under normal conditions, the tail is important in order to maintain the functioning of nerve cells. In contrast, in the case of prion infections the pathogenic prion protein interacts with the globular part and the tail causes cell death.

Proteins with similarities to prions also play a role in the pathogenesis of other diseases, such as Creutzfeldt-Jakob disease and possibly some forms of Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s disease. Aguzzi et al suggest that prion tail-mediated toxicity could conceivably play a role in these conditions, and that it may be worthwhile screening patients with idiopathic neurodegeneration for disease-causing autoantibodies.

Currently there is no epidemiological evidence for the spreading and/or acceleration of other protein misfolding diseases due to the transfer of misfolded proteins via natural or iatrogenic routes – that is, no evidence that Alzheimer’s, Parkinson’s or Huntington’s disease are infectious in the same way that CJD and other transmissible spongiform encephalopathies (TSEs) are. Such epidemiological evidence may be difficult to interpret for many of these diseases given their multifactorial etiologies and typically long preclinical and clinical phases. However, given the high incidence of diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s (ALS), it is important to know whether even a small percentage of cases can be initiated by transmission events. Even in the absence of significant human-to-human transmission routes, it is critical to establish whether prion-like propagation of protein misfolding within individuals can be observed and manipulated to alter the course of disease.

Know what triggers prion proteins to cause trouble also provides a possible route of preventing or at least slowing down such diseases. You can bet that a lot of investigators will be looking for triggering antiboes in a wide range of such diseases over the next few years. And if they find them, we can start working on ways to defeat these conditions.


Prions and the Potential Transmissibility of Protein Misfolding Diseases. (2013) Annual Review of Microbiology, 67 doi: 10.1146/annurev-micro-092412-155735
Prions, or infectious proteins, represent a major frontier in the study of infectious agents. The prions responsible for mammalian transmissible spongiform encephalopathies (TSEs) are due primarily to infectious self-propagation of misfolded prion proteins. TSE prion structures remain ill-defined, other than being highly structured, self-propagating, and often fibrillar protein multimers with the capacity to seed, or template, the conversion of their normal monomeric precursors into a pathogenic form. Purified TSE prions usually take the form of amyloid fibrils, which are self-seeding ultrastructures common to many serious protein misfolding diseases such as Alzheimer’s, Parkinson’s, Huntington’s and Lou Gehrig’s (amytrophic lateral sclerosis). Indeed, recent reports have now provided evidence of prion-like propagation of several misfolded proteins from cell to cell, if not from tissue to tissue or individual to individual. These findings raise concerns that various protein misfolding diseases might have spreading, prion-like etiologies that contribute to pathogenesis or prevalence.


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