Prion Hypothesis Research Articles

The prion hypothesis in Parkinson's disease: Braak to the future

Parkinson’s disease (PD) is a progressive neurodegenerative disorder typified by the presence of intraneuronal inclusions containing aggregated alpha synuclein (αsyn). The progression of parkinsonian pathology and clinical phenotype has been broadly demonstrated to follow a specific pattern, most notably described by Braak and colleagues. In more recent times it has been hypothesized that αsyn itself may be a critical factor in mediating transmission of disease pathology from one brain area to another. Here we investigate the growing body of evidence demonstrating the ability of αsyn to spread transcellularly and induce pathological aggregation affecting neurons by permissive templating and provide a critical analysis of some irregularities in the hypothesis that the progression of PD pathology may be mediated by such a prion-like process. Finally we discuss some key questions that remain unanswered which are vital to determining the potential contribution of a prion-like process to the pathogenesis of PD.

Convergent Replication of Mouse Synthetic Prion Strains

Prion diseases are neurodegenerative disorders characterized by the aberrant folding of endogenous proteins into self-propagating pathogenic conformers. Prion disease can be initiated in animal models by inoculation with amyloid fibrils formed from bacterially derived recombinant prion protein. The synthetic prions that accumulated in infected organisms are structurally distinct from the amyloid preparations used to initiate their formation and change conformationally on repeated passage. To investigate the nature of synthetic prion transformation, we infected mice with a conformationally diverse set of amyloids and serially passaged the resulting prion strains. At each passage, we monitored changes in the biochemical and biological properties of the adapting strain. The physicochemical properties of each synthetic prion strain gradually changed on serial propagation until attaining a common adapted state with shared physicochemical characteristics. These results indicate that synthetic prions can assume multiple intermediate conformations before converging into one conformation optimized for in vivo propagation.

Human prion diseases: Molecular, cellular and population biology

The past 20 years have witnessed a dramatic resurgence of interest in a hitherto obscure neurodegenerative disease, Creutzfeldt‐Jakob disease (CJD). This was driven partly by the novelty of the prion hypothesis, which sought to provide an explanation for the pathogenesis of transmissible spongiform encephalopathies, involving a unique epigenetic mechanism, and partly by events in the UK, where an outbreak of a new prion disease in cattle (bovine spongiform encephalopathy or BSE) potentially exposed a large section of the UK population to prion infectivity through a dietary route. The numbers of cases of the resultant novel disease variant CJD (vCJD), have so far been limited and peaked in the UK in the year 2000 and have subsequently declined. However, the effects of BSE and vCJD have been far‐reaching. The estimated prevalence of vCJD infection in the UK is substantially higher than the numbers of clinical cases would suggest, posing a difficult dilemma for those involved in blood transfusion, tissue transplantation and cellular therapies. The clinico‐pathological phenotype of human prion diseases has come under close scrutiny and molecular classification systems have been developed to account for the different diseases and their phenotypic spectra. Moreover, enhanced human and animal surveillance and better diagnostic tools have identified new human and animal prion diseases. Lastly, as the prion hypothesis has gained widespread acceptance, the concepts involved have been applied to other areas, including extra‐chromosomal inheritance in fungi, long‐term potentiation in memory formation and the spread of molecular pathology in diverse conditions, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Studies at the molecular and cellular level have helped to provide a better understanding of human prion diseases, aided pathological diagnosis and helped inform public health decision‐making.

The prion dilemma confounding science educators

In this paper, the issue of the prion hypothesis, a simmering controversy within the scientific community, is addressed. We inquire into the appropriateness of the use of certain augmentations and rhetoric approaches used during scientific debates, as well as the aptness of unequivocal statements in textbooks that indicate “abnormal prions” as a primary cause of Transmissible Spongiform Encephalopathies.

The prion dilemma confounding science educators

In this paper, the issue of the prion hypothesis, a simmering controversy within the scientific community, is addressed. We inquire into the appropriateness of the use of certain augmentations and rhetoric approaches used during scientific debates, as well as the aptness of unequivocal statements in textbooks that indicate “abnormal prions” as a primary cause of Transmissible Spongiform Encephalopathies.

Is it all about Contact? Neurodegeneration as a “Protein Freeze Tag Game” Inside the Central Nervous System

Is it all about Contact? Neurodegeneration as a “Protein Freeze Tag Game” Inside the Central Nervous System

From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases

Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrPSc, an abnormal β-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSc can trigger the autocatalytic conversion of PrPC into PrPSc, presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of “deformed templating” regarding a new mechanism of PrPSc formation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease and tauopathies.

Long double stranded RNA is present in scrapie infected cells and tissues

Despite decades of research efforts, the nature of the infectious agent causing scrapie and other Transmissible Spongiform Encephalopathies (TSE) remains an enigma. The protein-only prion hypothesis posits that an abnormal conformer of a host protein is the infectious agent. Virus and virino theories include host-independent nucleic acids in the genome of the infectious agent, in addition to the protein component (a host protein in the case of virino, and a viral protein in the case of a virus). Viral or sub-viral nucleic acids have long been sought in scrapie to explain the existence of multiple agent strains. Despite a plethora of different approaches to the search, no scrapie-specific nucleic acid sequences have been found in infected cells or tissues. Most viruses induce synthesis of long double stranded RNA (dsRNA) during their replication in cells, and thus the presence of long dsRNA would be an indication of viral infection in cells. J2 monoclonal antibody against long dsRNA is a useful tool for easy screening of cells and tissues for the presence of suspected viral infection; however, this antibody has not previously been used for testing of scrapie infected tissues. Here, we present evidence for long dsRNA in scrapie infected cells and tissues. Such dsRNA is also found in scrapie free tissue culture cells. We believe this may be the first evidence of viral infection in scrapie susceptible and infected cells.

Long double stranded RNA is present in scrapie infected cells and tissues

Despite decades of research efforts, the nature of the infectious agent causing scrapie and other Transmissible Spongiform Encephalopathies (TSE) remains an enigma. The protein-only prion hypothesis posits that an abnormal conformer of a host protein is the infectious agent. Virus and virino theories include host-independent nucleic acids in the genome of the infectious agent, in addition to the protein component (a host protein in the case of virino, and a viral protein in the case of a virus). Viral or sub-viral nucleic acids have long been sought in scrapie to explain the existence of multiple agent strains. Despite a plethora of different approaches to the search, no scrapie-specific nucleic acid sequences have been found in infected cells or tissues. Most viruses induce synthesis of long double stranded RNA (dsRNA) during their replication in cells, and thus the presence of long dsRNA would be an indication of viral infection in cells. J2 monoclonal antibody against long dsRNA is a useful tool for easy screening of cells and tissues for the presence of suspected viral infection; however, this antibody has not previously been used for testing of scrapie infected tissues. Here, we present evidence for long dsRNA in scrapie infected cells and tissues. Such dsRNA is also found in scrapie free tissue culture cells. We believe this may be the first evidence of viral infection in scrapie susceptible and infected cells.

Long double stranded RNA is present in scrapie infected cells and tissues

Despite decades of research efforts, the nature of the infectious agent causing scrapie and other Transmissible Spongiform Encephalopathies (TSE) remains an enigma. The protein-only prion hypothesis posits that an abnormal conformer of a host protein is the infectious agent. Virus and virino theories include host-independent nucleic acids in the genome of the infectious agent, in addition to the protein component (a host protein in the case of virino, and a viral protein in the case of a virus).Viral or sub-viral nucleic acids have long been sought in scrapie to explain the existence of multiple agent strains. Despite a plethora of different approaches to the search, no scrapie-specific nucleic acid sequences have been found in infected cells or tissues.Most viruses induce synthesis of long double stranded RNA (dsRNA) during their replication in cells, and thus the presence of long dsRNA would be an indication of viral infection in cells. J2 monoclonal antibody against long dsRNA is a useful tool for easy screening of cells and tissues for the presence of suspected viral infection; however, this antibody has not previously been used for testing of scrapie infected tissues.Here, we present evidence for long dsRNA in scrapie infected cells and tissues. Such dsRNA is also found in scrapie free tissue culture cells. We believe this may be the first evidence of viral infection in scrapie susceptible and infected cells.

Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders

Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrP(res)), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders.

Failure of Prion Protein Oxidative Folding Guides the Formation of Toxic Transmembrane Forms

The mechanism by which pathogenic mutations in the globular domain of the cellular prion protein (PrP(C)) increase the likelihood of misfolding and predispose to diseases is not yet known. Differences in the evidences provided by structural and metabolic studies of these mutants suggest that in vivo folding could be playing an essential role in their pathogenesis. To address this role, here we use the single or combined M206S and M213S artificial mutants causing labile folds and express them in cells. We find that these mutants are highly toxic, fold as transmembrane PrP, and lack the intramolecular disulfide bond. When the mutations are placed in a chain with impeded transmembrane PrP formation, toxicity is rescued. These results suggest that oxidative folding impairment, as on aging, can be fundamental for the genesis of intracellular neurotoxic intermediates key in prion neurodegenerations.

Long double stranded RNA is present in scrapie infected cells and tissues

AbstractThe nature of the infectious agent causing scrapie and other Transmissible Spongiform Encephalopathies remains an enigma despite decades of research efforts. The protein-only prion hypothesis posits that abnormal conformer of a host protein is the infectious agent. Virus and virino theories include host-independent nucleic acid as the genome of the infectious agent in addition to protein component (in case of virino a host protein and in case of virus a viral protein). Viral or sub-viral nucleic acids have long been sought in scrapie to explain the existence of multiple agent strains. Many different approaches were undertaken to find such nucleic acid. Despite that no scrapie specific nucleic acid sequences have been found in infected cells or tissues. Most viruses induce synthesis of long double stranded RNA (dsRNA) during their replication in cells. Therefore the presence of long dsRNA would be an indication of viral infection in cells. J2 monoclonal antibody against long dsRNA is a great tool for easy screening of cells and tissues for the presence of suspected unknown viral infection. This antibody has not been used for testing of scrapie infected tissues.Evidence is presented here for long dsRNA in scrapie infected cells and tissues. Such dsRNA is also found in scrapie free tissue culture cells.

New Evidence for Prion Hypothesis

New Evidence for Prion Hypothesis

Generalization of the Prion Hypothesis to Other Neurodegenerative Diseases: An Imperfect Fit

Protein misfolding diseases have been classically understood as diffuse errors in protein folding, with misfolded protein arising autonomously throughout a tissue due to a pathologic stressor. The field of prion science has provided an alternative mechanism whereby a seed of pathologically misfolded protein, arising exogenously or through a rare endogenous structural fluctuation, yields a template to catalyze misfolding of the native protein. The misfolded protein may then spread intercellularly to communicate the misfold to adjacent areas and ultimately infect a whole tissue. Mounting evidence implicates a prion-like process in the propagation of several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and the tauopathies. However, the parallels between the events observed in these conditions and those in prion disease are often incomplete. The aim of this review was to examine the current state of knowledge concerning the mechanisms of protein misfolding and aggregation for neurodegeneration-associated proteins. In addition, possible methods of intercellular spread are described that focus on the hypothesis that released microvesicles function as misfolded protein delivery vehicles, and the therapeutic options enabled by viewing these diseases from the prion perspective.

The Relevance of Scientific Practice to The Problem of Coordination

In his early work on the problem of coordination, Hans Reichenbach introduced axioms of coordination to describe the relationship between theory and observation. His insistence that these axioms are determinable a priori, however, causes him to ignore the normative dimensions of scientific inquiry and, in turn, generates a misleading interpretation of the theory-observation relationship. In response, I propose an alternative approach that describes this relationship through the framework of scientific practices. My argument will draw on two examples that have not been explored by the philosophical literature in the context of coordination problems: the clinical definition of death and Stanley Prusiner’s prion hypothesis.

De novo generation of prion strains.

Prions are self-replicating proteins that can cause neurodegenerative disorders such as bovine spongiform encephalopathy (also known as mad cow disease). Aberrant conformations of prion proteins accumulate in the central nervous system, causing spongiform changes in the brain and eventually death. Since the inception of the prion hypothesis - which states that misfolded proteins are the infectious agents that cause these diseases - researchers have sought to generate infectious proteins from defined components in the laboratory with varying degrees of success. Here, we discuss several recent studies that have produced an array of novel prion strains in vitro that exhibit increasingly high titres of infectivity. These advances promise unprecedented insight into the structure of prions and the mechanisms by which they originate and propagate.

Conformational conversion and prion disease

Because of mechanistic similarities between prion propagation in mammals and fungi, Tuite and Serio recently proposed (The prion hypothesis: from biological anomaly to basic regulatory mechanism. Nature Rev. Mol. Cell Biol. 11, 823–833 (2010))1 that similarly to fungal prions, which are thought to act as phenotype regulators, prions in mammals should be considered as a basic regulatory mechanism instead of a biological anomaly. However, by considering the behaviour of prions, we argue that the fact that mammalian and fungal prions use a similar mechanism of conformational conversion is not enough to suggest that they are not just infectious agents.

Conformational conversion and prion disease: authors' reply

In their correspondence to our article (The prion hypothesis: from biological anomaly to basic regulatory mechanism. Nature Rev. Mol. Cell Biol. 11, 823–833 (2010)), Shen and Ji (Conformational conversion and prion disease. Nature Rev. Mol. Cell Biol. 23 Mar 2011 (doi:10.1038/nrm3007-c1)) disagree with the central opinion that, in light of the emerging information on the phenotypic impact of fungal prions, we can no longer consider mammalian prion proteins as just infectious agents that cause disease. The concern raised by Shen and Ji, we believe, is largely a semantic one, and we hope that this response helps clear up any ambiguity that some readers of our article may have had.

PrPSc spreading patterns in the brain of sheep linked to different prion types

Scrapie in sheep and goats has been known for more than 250 years and belongs nowadays to the so-called prion diseases that also include e.g. bovine spongiform encephalopathy in cattle (BSE) and Creutzfeldt-Jakob disease in humans. According to the prion hypothesis, the pathological isoform (PrPSc) of the cellular prion protein (PrPc) comprises the essential, if not exclusive, component of the transmissible agent. Currently, two types of scrapie disease are known - classical and atypical/Nor98 scrapie. In the present study we examine 24 cases of classical and 25 cases of atypical/Nor98 scrapie with the sensitive PET blot method and validate the results with conventional immunohistochemistry. The sequential detection of PrPSc aggregates in the CNS of classical scrapie sheep implies that after neuroinvasion a spread from spinal cord and obex to the cerebellum, diencephalon and frontal cortex via the rostral brainstem takes place. We categorize the spread of PrPSc into four stages: the CNS entry stage, the brainstem stage, the cruciate sulcus stage and finally the basal ganglia stage. Such a sequential development of PrPSc was not detectable upon analysis of the present atypical/Nor98 scrapie cases. PrPSc distribution in one case of atypical/Nor98 scrapie in a presumably early disease phase suggests that the spread of PrPSc aggregates starts in the di- or telencephalon. In addition to the spontaneous generation of PrPSc, an uptake of the infectious agent into the brain, that bypasses the brainstem and starts its accumulation in the thalamus, needs to be taken into consideration for atypical/Nor98 scrapie.