ABSTRACT
The term “prion” was originally coined to describe the proteinaceous infectious agents involved in mammalian neurological disorders. More recently, a prion has been defined as a nonchromosomal, protein-based genetic element that is capable of converting the copies of its own benign variant into the prion form, with the new phenotypic effects that can be transmitted through the cytoplasm. Some prions are toxic to the cell, are able to aggregate and/or form amyloid structures, and may be infectious in the wild, but none of those traits are seen as an integral property of all prions. We propose that the definition of prion should be expanded, to include the inducible transmissible entities undergoing autocatalytic conversion and consisting of RNA rather than protein. We show that when seen in this framework, some naturally occurring RNAs, including ribozymes, riboswitches, viroids, viroid-like retroelements, and PIWI-interacting RNAs (piRNAs), possess several of the characteristic properties of prions.
KEYWORDS: piRNA, prions, ribozymes, viroids
OPINION/HYPOTHESIS
Mammalian prions: a classical definition. The studies of a peculiar class of infectious diseases in mammals, i.e., transmissible spongiform encephalopathies (TSEs), and the hunt for the elusive agent that causes these diseases, resulted in the notion of an infectious protein, or “prion.” The known prion-caused TSEs include kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia in humans, as well as scrapie, bovine spongiform encephalopathy, chronic wasting disease, and several other related diseases in mammals. The early evidence in favor of the protein-only agent for scrapie was based on the observations that the infectious subcellular fraction was highly resistant to UV irradiation, unlike the nucleic acids (summarized in reference
1), that the protocol for purification of the infectious moiety required the conditions used to purify certain proteins rather than RNA, and that the estimated molecular weight and other properties of the main component of such a fraction were close to that of a modest-size protein rather than, for example, a virus nucleic acid (
2,
3). This was backed up with experiments designed to exclude a role of small infectious RNAs, in particular viroids, in the etiology of scrapie (
4,
5). As early as in 1967, John S. Griffith outlined several possible mechanisms by which a protein could become inherited as a nonchromosomal genetic element. One of those hypothetical mechanisms stated that a prion is a modified form of a cognate cellular protein, which may bind to the normal form of the same protein (in the simplest case, forming a heterodimer of one prion and one normal copy of the protein) and then turn the normal form into another copy of the prion (
6). This predicted mechanism was borne out by the evidence and is at the core of the current definition of any prion.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333576/
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