The Prion concept
Prions are self-perpetuating protein isoforms that are transmitted via extracellular infection in mammals or inherited via the cytoplasm in lower eukaryotes such as yeast and other fungi. Most prions are transmissible amyloids (ordered fibrous cross-β aggregates). The mammalian prion protein (PrP), in its prion form, causes fatal transmissible encephalopathies such as “mad cow disease”. About 50 diseases in humans, including such neurodegenerative disorders as Alzheimer, Parkinson and Huntington diseases, are also associated with amyloids or amyloid-like depositions. Like prions, some of these amyloids can also be transmitted between cells. Many amyloid diseases are fatal and incurable. Some, such as Alzheimer disease are age-dependent and widespread, portending a large increase in health care costs as the population ages.
Some yeast prions are also pathogenic to the yeast host. However, recent evidence indicates that traits controlled in a prion-like fashion are present in at least about 1/3 of the natural or industrial isolates of the Saccharomyces cerevisiae yeast confirming that prions widespread, and possibly not all of them are toxic.
Fungal prions are epigenetic determinans that can radically change the phenotype of the host by altering a range of cellular processes, including metabolism and gene expression pathways. The prion mechanism provides a robust, but dynamic system for epigenetic regulation of phenotype controlled by the cellular and environmental factors. Some non-prion amyloids are shown to be involved in adaptive processes
Prion is thought to spread via nucleated polymerization; a polymeric prion “seed” or "nucleus" recruits a normally folded protein of the same amino acid sequence and converts it into an amyloid-like prion conformation. De novo formation of prion nuclei is facilitated when prion-forming protein is present at high local concentration. This process is best understood in yeast, where de novo prion can be induced by transient overproduction of a prion-forming protein or. Aggregates of other prionogenic proteins may cross-seed prion nucleation. In human Alzheimer's disease, the aggregation of amyloid β is also frequently accompanied by aggregation of another protein, tau. In mammals and humans, very little is known about environmental factors that can induce amyloids, although a prominent example is exposure to a pesticide linked to Parkinson disease. In yeast, prion formation is facilitated by incubation at low temperature, and by a variety of other environmental stresses including heat shock, osmotic and oxidative stresses, and the unfolded protein response. Mechanisms by which stressful conditions influence prion formation remain largely unknown.
Conditions affecting protein levels and homeostasis, such as alteration of the ubiquitin-proteasome system (UPS) influence formation and propagation of yeast prions and have been linked to some aggregation-related neurodegenerative diseases. UPS failure is associated with the accumulation and aggregation of misfolded proteins, potentially providing sites for enhanced nucleation of prions and other amyloids.
Intracellular deposits of amyloid aggregates contain significant amounts of ubiquitin (Ub) and other UPS components, although it is not likely that the UPS can directly degrade large amyloid deposits. Proteasome inhibitors affect the turnover of some amyloid and prion proteins, and proteasome activity is inhibited by amyloid disease-associated oligomers.
The emerging picture is that chaperones, Ub and UPS regulate sequestration of aggregated proteins into large deposits, perhaps as a cytoprotective response to accumulation of toxic abnormal proteins.However, localization of misfolded proteins to specific sites of disposal in the cell may also increase local protein concentrations, leading to nucleation of prion aggregates. Thus, such compartments could serve as prion-inducing sites. It is possible that some heterologous prion inducers may act by directing localization of prionogenic proteins to these compartments.
One possibility is that environmental stresses may act via influencing intracellular concentrations of the prionogenic and/or heterologous prion-inducing proteins, or by localizing (perhaps via heterologous ancillary proteins) prionogenic proteins to the prion induction sites. This may trigger the formation of many amyloids (both pathological and adaptive) in response to environmental signals. Such a scenario may present new opportunities for pharmacological interventions that target a core regulatory mechanism rather than the properties of individual prions, and lead to development of the prophylactic measures aimed at amyloid disorders, that typically result in even larger healthcare cost savings than therapeutic treatments.