What is prion disease?
A prion is a misfolded protein that can serve as a template for proteins of the same type to misfold, producing globs of non-functioning protein, causing cells to degenerate.
Prions of Yeast and Fungi
R.B. Wickner, ... D. Kryndushkin, in Encyclopedia of Virology (Third Edition), 2008
Shuffling Prion Domains and Amyloid Structure
The prion domains (Figure 2) of Ure2p and Sup35p are quite rich in Asn and Gln residues, and nearly the entire sequence of Rnq1p, the basis of the [PIN] prion, is rich in these amino acids. However, many Q/N-rich proteins are not capable of being prions. Thus, it was assumed that specific sequences in the known prion domains were important for prion formation. The Sup35 prion domain has octapeptide repeats much like those in PrP, and deletion or duplication of these showed substantial effects on prion generation. In addition, single amino acid changes in the prion domain of Sup35p blocked prion propagation.
To critically test whether the Ure2p prion domain had sequences essential for prion development, the entire Q/N-rich region (residues 1–89) was randomly shuffled (without changing the amino acid content) and each of five shuffled sequences were inserted into the chromosome in place of the normal prion domain. Surprisingly, each of these five shuffled sequences could support prion generation and propagation, although one was rather unstable. Each protein with the shuffled sequence could also form amyloid (Figure 3) in vitro. This showed that it was the amino acid content of the Ure2p prion domain that determines prion formation, and that sequence plays only a minor role.
Similarly, five shuffled versions of the Sup35p prion domain were each inserted in place of the normal sequence. Again, all five shuffled versions allowed formation and propagation of a [PSI]-like prion. It is likely that the effects of deletion or duplication of the octapeptide repeats observed on prion formation or propagation were due to changes in the length or composition of the prion domain. It appears that repeats per se are not important for prion generation or propagation.
Human Prion Diseases
Abigail B. Diack, Jason C. Bartz, in Handbook of Clinical Neurology, 2018
Prion strains are operationally defined as a heritable phenotype of disease under controlled transmission conditions. Several biochemical features of the infectious agent, PrPTSE, correspond with distinct prion strains, consistent with the hypothesis that prion strain diversity is encoded in the conformation of PrPTSE. Work on prion strain diversity and many other aspects of prion biology would not be possible without the development and advancement of powerful transgenic animal models of prion disease. Transgenic mice expressing exogenous PrPC have allowed for a wide range of investigative studies into the impact of human polymorphisms and/or mutations on disease transmission and pathogenesis. These models allow us to define disease processes with the aim of identifying therapeutic targets and ultimately disease interventions. It is only with a combination of an increased understanding of prion strain diversity, basic prion biology, and use of transgenic models that we will become closer to a cure for these devastating diseases.
Prions and Neurodegenerative Diseases
Sara A.M. Holec, ... Jason C. Bartz, in Progress in Molecular Biology and Translational Science, 2020
2.1 Prion strain diversity in yeast
Studies of yeast prion strain diversity have added much to the knowledge of prion strain diversity. Yeast prion strains differ in strength of phenotype, stability of propagation, toxicity/lethality, ability to overcome inter- or intraspecies transmission barriers, and biochemical and physical properties.57–59,65–67 Nuclear magnetic resonance (NMR) spectroscopy identified conformational differences between [PSI +] yeast prion strains, and atomic force microscopy (AFM) reveals strain-specific differences in yeast prion fibril morphology.68 There are strong correlations between biochemical properties of the prion form of the protein and strain phenotype in yeast. The strength of the yeast prion phenotype corresponds with an increased fragility of protein aggregates.69 Mechanistically, increased fragility of prion aggregates results in rapid generation of new free ends, accelerating prion formation
Mechanistic location of therapeutic targets for PrP prion diseases. Therapeutic targets: ❶ PrPC post-translational processing, metabolism, cellular trafficking, or localization; ❷ PrPC by binding or inducing conformational change that prevents PrPC interaction; ❸ PrPSc by stabilization, redistribution; ❹ conversion process by blocking binding site on PrPC, capping growth, inhibition of cofactor interactions, or ❺ promoting fragmentation or ❻ clearance from the host.
Proteins and Disease | Prions of Yeast and Fungi: Proteins Acting as Genes☆
Reed B. Wickner, Vivian Kitainda, in Encyclopedia of Biological Chemistry (Third Edition), 2021
[PIN+] was discovered as a nonchromosomal gene whose presence was necessary for the efficient induction of the de novo appearance of [PSI+] by overexpression of Sup35p. [PIN+] was found to be a prion of the Rnq1 protein, which had already been shown capable of a self-propagating aggregation in vivo. In fact, [URE3] is also capable of [PIN+]-like activity. This showed that one prion could promote the generation of another. This may be because all of these prions ([PSI+], [PIN+], and [URE3]) are based on amyloid of asparagine-glutamine rich segments. Although cross-priming of polymerization is not as efficient as self-priming (the usual propagation reaction), it is far more efficient than the truly spontaneous development of a prion. A similar, though weaker, effect of [PIN+] on [URE3] generation has also been observed (Wickner et al., 2008b).
Prion generation is also diminished by the Hsp70-group chaperones Ssb1p and Ssb2p. Both are ribosome associated, and are believed to help nascent peptides fold properly. It will be of great interest to understand the mechanisms by which Ssb’s block prion formation (Sharma and Masison, 2009).
Human Prion Diseases
Suzette A. Priola, in Handbook of Clinical Neurology, 2018
Role of PrPC
Prion strain-specific cofactors could dictate whether or not a given prion strain can establish a persistent infection in vitro and thus might control the switch from acute to persistent prion infection. However, no strain-specific protein cofactors have been found in close association with PrPTSE (Moore et al., 2010) and there is no evidence of nonprotein molecules interacting with PrPTSE in a prion strain-specific manner. By contrast, there is some evidence that GPI anchoring of PrPC to the plasma membrane is necessary for the transition from acute to persistent prion infection in vitro. Changing the GPI anchor of PrPC to a transmembrane anchor inhibits its conversion to PrPTSE (Taraboulos et al., 1995; Kaneko et al., 1997; Marshall et al., 2017), suggesting that the localization of PrPC to lipid rafts via its GPI anchor is necessary for PrPTSE formation. By contrast, during the acute phase of prion infection PrPC without the GPI anchor can be converted to PrPTSE, albeit with a lower efficiency, suggesting that membrane anchoring is not required for acute PrPTSE formation (McNally et al., 2009). However, cells expressing PrPC without the GPI anchor cannot support either persistent replication of GPI anchorless PrPTSE or persistent prion infection unless wild-type GPI-anchored PrPC is present (McNally et al., 2009). Thus, while the GPI anchor is not essential for formation of PrPTSE in vitro, the presence of GPI-anchored PrPTSE appears to be required in the transition from acute to persistent prion infection.
In Virus Taxonomy, 2012
Similarity with other taxa
The N-terminal prion domain of Sup35p includes repeat aa sequences similar to the octapeptide repeats in PrP, but the Sup35p repeats are not necessary for prion formation as shuffling the Sup35p prion domain does not prevent amyloid formation. The Sup35 prion domains of Candida albicans, Kluyveromyces lactis and Pichia methanolica can be prion domains in S. cerevisiae when fused to the S. cerevisiae Sup35MC (non-prion) domain. Full length Ure2p from S. bayanus, S. uvarum, S. mikatae, S. cariocanus and S. paradoxus can form the [URE3] prion in S. cerevisiae.
Overall, the yeast and fungal prions are analogous to the mammalian prion protein PrP, but not at all homologous.
Early Stage Protein Misfolding and Amyloid Aggregation
K.S. MacLea, in International Review of Cell and Molecular Biology, 2017
3.5 Prions in Other Eukaryotes
Prion-based TSEs have only been reported in mammals. However, homologs of the PrP-encoding gene have been identified in birds, reptiles, amphibians, and fish (reviewed in Málaga-Trillo et al., 2011; Schätzl, 2007). It is unknown whether the variant PrP sequences in these species (which have several divergent features depending on taxonomic grouping) can form bona fide prions, amyloids, or whether TSE-like disease is present in these animals.
A protein with prion characteristics, when expressed in the yeast system, was also recently found in Arabidopsis, making it the first potential plant prion-like protein (Chakrabortee et al., 2016; discussed in Chernoff, 2016).
Organizational Cell Biology
G. Legname, K.E. Pischke, in Encyclopedia of Cell Biology, 2016
Prion strains are molecules that share the same primary sequence of amino acids, but with differing incubation times or neuropathological/biochemical properties. Strains are believed to result from conformational differences in PrPSc (Telling et al., 1996).
The existence of prion strains was first shown by the transmission of two isolates from scrapie-infected sheep into goats. It was observed that the goats showed two marked behavioral pathologies, a drowsy syndrome and a scratching syndrome, and that these behaviors were conserved upon subsequent passages in goats (Pattison and Millson, 1961). Later, five prion scrapie strains were isolated following inoculation into mice. These strains could be reliably recognized by histological parameters (degree of vacuolation and relative distribution of the damage within the brain) (Fraser and Dickinson, 1973). Additional studies have identified many prion strains with persisting characteristics after serial transmission in rodents (Solforosi et al., 2013).
It was hard to imagine at the time that all of this diversity could be encoded simply within the protein structure of PrPSc. It was widely thought that the existence of strains was convincing evidence that some nucleic acid, which could mutate, must be involved. Even several genes within the host genome were suspected of influencing prion strains; but this was disproven when prion strains were propagated in vitro via nongenetic mechanisms (Bessen et al., 1995).
Direct evidence for the molecular basis of prion strains was long wanting and many looked at prion strains as a key obstacle to the protein-only hypothesis. Ultimately, it was shown that hamsters infected with two strains of TME resulted in PrPSc molecules with distinct electrophoretic mobility (revealed as a specific pattern of bands on a Western Blot) and degree of resistance to protease digestion (Bessen and Marsh, 1994). The observed diversity is thought to arise from varying three-dimensional structures resulting in exposure of different combinations of proteinase-K cleavage sites found on the PrP (Parchi et al., 2000). Unique banding patterns have also been described for protease-resistant PrP originating from vCJD and FFI (Collinge et al., 1996; Telling et al., 1996).
Prion strains are defined by their distinct prion disease phenotype (incubation time to disease onset, histopathological lesion profiles, and brain areas targeted) that persists upon serial transmission. Molecularly, strains have been described by their band pattern on a Western Blot after protease digestion and degree of protease digestion. In addition, pathological features are instrumental for fine characterization of closely related prion disorders.
Prions and Neurodegenerative Diseases
Ilia V. Baskakov, in Progress in Molecular Biology and Translational Science, 2020
Mammalian prion or PrPSc is a proteinaceous infectious agent that consists of a misfolded, self-replicating state of a sialoglycoprotein called the prion protein or PrPC. Sialylation of the prion protein, a terminal modification of N-linked glycans, was discovered more than 30 years ago, yet the role of sialylation in prion pathogenesis is not well understood. This chapter summarizes current knowledge on the role of sialylation of the prion protein in prion diseases. First, we discuss recent data suggesting that sialylation of PrPSc N-linked glycans determines the fate of prion infection in an organism and control prion lymphotropism. Second, emerging evidence pointing out at the role N-glycans in neuroinflammation are discussed. Thirds, this chapter reviews a mechanism postulating that sialylated N-linked glycans are important players in defining strain-specific structures. A new hypothesis according to which individual strain-specific PrPSc structures govern selection of PrPC sialoglycoforms is discussed. Finally, this chapter explain how N-glycan sialylation control the prion replication and strain interference. In summary, comprehensive review of our knowledge on N-linked glycans and their sialylation provided in this chapter helps to answer important questions of prion biology that have been puzzling for years.
Human Prion Diseases
Thomas Wisniewski, Fernando Goñi, in Handbook of Clinical Neurology, 2018
Prion-like phenomena are increasingly being recognized to be part of the pathogenesis of numerous common human neurodegenerative diseases, including AD. Many encouraging experimental antiprion vaccine strategies have been reported. Passive immunization, immediately or shortly after exposure, has been successful in mouse models, preventing disease. In addition mucosal immunization has been shown to potentially prevent prion infection via an oral route in mouse models as well as in deer. The latter approach, with further refinement, would be potentially highly appropriate to stem the epidemic of CWD in North America and the recent emergence of CWD in Northern Europe. However, for effective immunotherapy near or at the time of clinical disease, methods to more specifically target PrPTSE, that will be effective in the brain, are needed. Active and passive immunization approaches that specifically target pathology-associated conformers such as PrPTSE, oligomeric Aβ, and paired helical filaments tau are currently under development and are being tested in both AD and prion models (Goni et al., 2013, 2015, 2016b, 2017; Marciniuk et al., 2014; Wisniewski and Goni, 2015; Drummond et al., 2018).
Neurobiology of Disease
Alzheimer's & Dementia
Journal of the Neurological Sciences