Elsevier

Virus Research

Volume 207, 2 September 2015, Pages 82-93
Virus Research

Prion and prion-like diseases in animals

https://doi.org/10.1016/j.virusres.2014.11.026Get rights and content

Highlights

  • In this review, we provide a description of the prion and prion-like diseases affecting animals.

  • We review the ability of certain non-prion proteins to misfold and self-propagate.

  • We review the recent findings suggesting the transmissibility of some prion-like diseases affecting animals.

Abstract

Transmissible spongiform encephalopaties (TSEs) are fatal neurodegenerative diseases characterized by the aggregation and accumulation of the misfolded prion protein in the brain. Other proteins such as β-amyloid, tau or Serum Amyloid-A (SAA) seem to share with prions some aspects of their pathogenic mechanism; causing a variety of so called prion-like diseases in humans and/or animals such as Alzheimer's, Parkinson's, Huntington's, Type II diabetes mellitus or amyloidosis. The question remains whether these misfolding proteins have the ability to self-propagate and transmit in a similar manner to prions. In this review, we describe the prion and prion-like diseases affecting animals as well as the recent findings suggesting the prion-like transmissibility of certain non-prion proteins.

Introduction

Prion diseases or Transmissible Spongiform Encephalopaties (TSEs) are fatal neurodegenerative diseases that affect a diversity of mammal species including Creutzfeldt–Jacob disease (CJD), kuru, Gerstmann-Sträussler-Scheinker disease (GSS), and familial fatal insomnia (FFI) in humans, as well as scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in deer and elk. Prion diseases are characterized by long incubation times (from months to decades), development of neuropathological alterations and symptoms primarily neurological including behavior abnormalities, motor dysfunction, cognitive impairment and cerebral ataxia. Prion diseases do not produce immune response and nowadays no effective therapies are available for their treatment.

Prion diseases are caused by the conversion of the physiological cellular prion protein (PrPC) into a pathogenic β-sheets enriched isoform designated PrPSc, which is able to self-propagate by recruiting PrPC. This conformational change confers PrPSc with an increased tendency to aggregate, insolubility in non-ionic detergents, high resistance to heat and chemical sterilization, and partial resistance to protease digestion. The concept of proteinaceous infectious particles, “Prions”, was first recapitulated in the “Prion Protein Only Hypothesis” (Prusiner, 1982). To date, a number of studies have supported this contention, including the successful induction of neurodegenerative diseases just from recombinant amyloid forms of prions (Castilla et al., 2005, Colby et al., 2009, Legname et al., 2004) or in combination with certain lipids and RNA factors (Wang et al., 2010). Nevertheless, some findings suggest that the misfolded PrPSc protein alone is not necessarily infectious by itself and needs some cofactors to self-propagate (Deleault et al., 2012, Saa et al., 2012, Telling et al., 1995). Hence, some authors proposed that PrPSc formation and infectious agent replication might constitute two separated processes where infectivity could lay on other non-PrP structures (reviewed in Manuelidis, 2013).

Despite these arguments, prion diseases are entirely dependent on the expression of endogenous PrPC, as confirmed by the total resistance of prnp knock-out mice to prion infection (Bueler et al., 1993, Prusiner et al., 1993). PrPC is a glycosylphosphatidylinositol (GPI)-anchored plasma membrane protein encoded by the prnp gene which is well conserved throughout evolution in mammals (Nicolas et al., 2009). PrPC is mostly expressed in central nervous system (CNS) but also in the lymphoreticular system (LRS), skeletal muscle, heart, kidney, digestive tract, skin, blood plasma, mammary gland and endothelia (Nuvolone et al., 2009). Despite its ubiquitous expression and distribution, its physiological function is not yet clear.

The mechanism by which PrPC converts into PrPSc adopting the capacity to self-template is neither well-known. PrPC can fold into a variety of thermodynamically stable PrPSc conformers (Prusiner, 1998, Wiltzius et al., 2009) whose mixture in a relative proportion may result in different prion strains (Angers et al., 2010). Each prion strain displays a specific disease phenotype (including incubation times, clinical signs, and histopathological lesions and PrPSc deposition patterns in the brain) which is faithfully recapitulated upon serial passage within the same host genotype (Beringue et al., 2008b, Collinge and Clarke, 2007). Prion strains may arise upon replication and transmission by “mutation” and/or “adaptation”. However, the molecular mechanism by which the range of PrPSc conformers would be produced and selected has not been yet elucidated. One possibility is that each PrPSc conformer might require a unique set of cofactors to propagate efficiently, and that the distribution and/or availability of these cofactors vary among different animal species, individuals or even distinct cell types. In line with this view, it was reported that different cell types within the same host can offer unique environments and selective pressures, each resulting in the emergence of different mutants as major constituents of the evolving population (Aguzzi and Sigurdson, 2004, Li et al., 2010, Mahal et al., 2007, Tremblay et al., 2004). On the other hand, studies in yeast have provided fundamental information for understanding the phenomenon of prion strain. A direct correlation between the frangibility (propensity to break) of yeast PrPSc fibrils and their rate of replication have been reported (Immel et al., 2007, Tanaka et al., 2004, Tanaka et al., 2006) and later extended to mammalian prions (Legname et al., 2006). Deciphering the structural features of PrPSc is a key issue to understand the molecular basis of prion formation, adaptation and propagation. Despite great efforts, the detailed tertiary structure of PrPSc is still unknown due to its insolubility and propensity to aggregate. Therefore, only partial structural information is available from low resolution techniques which failed to produce a shared explanation for the infectious capacity of prions (reviewed in Requena and Wille, 2014).

The ability to misfold and self-propagate is not exclusive of prion proteins. Several neurodegenerative and non-neurodegenerative disorders are associated with the accumulation of self-templating amyloid forms of specific proteins in various organs and tissues of animals and humans. This heterogeneous group of diseases, called amyloidosis, are caused by the conformational change of a physiologically soluble protein into a β-sheet enriched form which self-assembly into amyloid fibrils. Similarly to prions, this conformational change triggers insolubility, aggregation and resistant to physical denaturants favoring the amyloid deposition and disrupting the physiological function of the tissues/organs where accumulates. The pathology and pathogenesis of amyloidosis are highly variable depending on the protein that causes the disease and the factors provoking this misfolding.

To date, at least 28 different misfolding proteins, also called amyloid precursors, have been reported in humans and animals; including tau and Amyloid Precursor Protein (APP) in Alzheimer's disease, huntingtin in Huntington's disease, Serum Amyloid-A (SAA) in systemic amyloidosis or islet amyloid polypeptide in Type II diabetes mellitus. The exact mechanism through which these misfolding proteins are transformed and aggregated remains unknown but is reminiscent of prion replication. Thereby, amyloidosis have been labeled as “prion-like diseases” and included in the group of protein misfolding disorders (PMDs); where prion diseases belong. Moreover, increasing evidences attribute potential prion-like infectious properties to some of these amyloid precursors. In this way, tau, β-amyloid and α-synuclein have the ability to spread cell to cell, as demonstrated in mammalian cell cultures, in animals or even in humans (Costanzo and Zurzolo, 2013, Prusiner, 2012, Soto, 2012). In contrast, transmission between individuals has not been documented so far. The current key question is the possible infectious nature of these so-called “prion-like diseases” in a similar manner of prion diseases. In this review, an updated description of the prion and “prion-like diseases” affecting animals is presented. Pathogenesis of “prion-like diseases” in comparison with prion diseases as well as recent findings supporting the amyloidosis transmissibility are highlighted too.

Section snippets

Prion diseases in animals

Prion diseases may occur as inherited disorders, arise spontaneously or be acquired by infection. Transmissions within the same animal species but also between different species have been reported for some prion diseases and at least one of them, the bovine spongiform encephalopathy (BSE), is considered a zoonosis to date.

Prion-like diseases in animals

In animals, at least eight different diseases associated to misfolded proteins or amyloid precursors have been described (Mensua et al., 2003). These diseases, called amyloidosis, may present as localized or systemic disorders (Sipe et al., 2012) with symptoms depending on the tissues where amyloid are deposited. Attending to their etiology, amyloidosis can be idiopathic, primary or secondary (associated to inflammatory or neoplastic pathologies) diseases. In animals, all of these forms have

Transmissibility of prion-like diseases

Prion-like misfolding and self-propagation have been demonstrated for several non-prion proteins including SAA, ApoII, tau, α-synuclein or β-amyloid. These misfolding proteins or amyloid precursors are responsible for the appearance of highly relevant neurodegenerative and non-degenerative diseases in human and animal species such as Alzheimer's disease, Huntigton's disease (HD), Parkinson's disease and Type II diabetes mellitus among others. Currently, the key question is whether these

Perspectives

The data summarized in this review strongly argue that a growing number of amyloid proteins could be considered infectious agents with the capacity to transmit through a prion-like mechanism involving seeding-nucleation (Lundmark et al., 2003). The efficient transmission of some amyloid precursors within certain animal species or even between different animal species prompts to the implementation of measurements for their control. The question remains whether amyloidogenic proteins has a

Conflict of interest

The authors declare no competing financial interests.

Acknowledgements

This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (AGL2012-37988-C04-04 and RTA2012-00004-00-00) and European Union (219235 FP7 ERA-NET EMIDA).

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