Infectious particles, stress, and induced prion amyloids: A unifying perspective
Volume 4, Issue 5 July 1, 2013
Keywords: Alzheimer disease, Parkinson disease, aging, biofilms, environmental pathogens, latency, metagenome, nucleic acids, transmissible encephalopathies, yeast prions
Authors: Laura Manuelidis
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Yale University Medical School; New Haven, CT USA
Abstract: Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrPSc) without nucleic acid. Many TSE agents reside in the environment with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging.
Received: March 12, 2013; Accepted: April 26, 2013; Published Online: April 30, 2013
The structure and strain-determining molecular components of infectious TSE particles remains unknown. An enormous variety of evidence contradicts the conclusion that TSE infectious agents are made of host PrP without nucleic acid or an environmental component. First, different agent strains give the same PrP-res pattern, and conversely, samples with very different PrP-res patterns can propagate the identical infectious agent. Thus observed PrP conformers do not encode or predict strains. Second, all forms of detectable PrP can be destroyed with no loss of infectivity. PrP has also been undetectable in cells with high infectious titers. Third, the host recognizes and mounts early innate immune defenses against individual TSE agents and this determines latency and incubation time. Fourth, PrP-res amyloid appears as part of a late defense mechanism against a foreign agent, and TSE agent replication demonstrates a vastly different trajectory than the conversion kinetics of PrP-res (the “infectious” form). Fifth, PrP acts as a required host receptor for agent survival. In this capacity it can protect the agent while allowing the host to survive for years. Sixth, as other GPI proteins, PrP facilitates cell-to-cell transfer, and can be used by several infectious agents, not just TSEs. Seventh, as in TSE infections, other viruses can induce misfolded protein “prion” aggregates as part of an antiviral innate immune response. Eighth, the ability to fold into an amyloid state is a property shared by many proteins and peptides.
Amyloid aggregation is a process that is highly conserved in evolution and it does not require infection. In yeast, such conversions are involved in a wide range of functions, including transcriptional and translational regulation.38 Dense resistant bacterial biofilms function in socialization and protection69 and can be considered together with mammalian amyloids, including PrP and AD plaques that contain many other elements.23 Infection poses additional unexplored opportunities. The discovery of bacterial plasmid-like elements associated with TSE infectious particles raises the issue of unsuspected exchanges between mammals and bacterial viral elements in disease. Some of these viral elements may be the root cause of TSEs as well as a diversity of chronic conditions. Alternatively, such elements may promote the aggregation of fibrillar proteins in neurodegenerations of unknown etiology. Metagenomic elements, along with environmental toxins, surely deserve broader attention as causal factors in AD and other late-onset diseases.