MicrobiologyBytes

Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrPC. They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrPC and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed.

An overview of human prion diseases. (2011) Virology Journal 8: 559 doi:10.1186/1743-422X-8-559

Tweet

The transmissible agent of prion disease consists of a prion protein in its abnormal conformation (PrP^Sc), which replicates itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrP^Sc. This new study reports that infectious prions and transmissible prion disease can be triggered in wild type animals by amyloid fibrils produced from recombinant prion prtotein, which are structurally different from PrP^Sc and lacks any detectable PrP^Sc particles.

This work introduces a new hypothesis that transmissible prion diseases can be induced by prion protein structures different from that of authentic PrP^Sc and suggests that a new mechanism for triggering PrP^Sc formation different from the classical templating exists. The current work provides important new insight into the mechanisms underlying genesis and evolution of the transmissible states of the prion protein and has numerous implications for understanding the etiology of prion and other neurodegenerative diseases.

Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease. (2011) PLoS Pathog 7(12): e1002419. doi:10.1371/journal.ppat.1002419
The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrP^Sc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrP^Sc template. Here we report that authentic PrP^Sc and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrP^Sc and lack any detectable PrP^Sc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (Pr^Pres) before authentic PrP^Sc evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrP^Sc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as “deformed templating” postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrP^Sc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases.

Tweet

The BSE epidemic cost us billions, and devastated the British farming industry. Now, that plague is at an end. Overall, as many as three million animals were infected; in the peak year, 1992, the UK saw 37,280 diagnoses. Yet there are good reasons why any celebrations have been put on hold. All told, around half a million infected animals entered the food chain. Although it remains unclear how many people ate the most infectious parts, it is clear that the majority of the British population was exposed. So far, the human equivalent of BSE, variant Creutzfeldt-Jakob disease (vCJD), has claimed 170 lives, mainly through consumption of BSE-infected beef. And because of the extraordinary incubation time of the disease, it is possible that many more cases may be waiting in the wings.

Read more: The end of BSE

Scientists have just challenged the notion that airborne prions are innocuous. It is known that prions can be transmitted through contaminated surgical instruments and, more rarely, through blood transfusions. However, prions are not generally considered to be airborne – in contrast to many viruses such as influenza and chicken pox. In the new study, the authors housed immunodeficient and immunocompetent mice in special inhalation chambers and exposed them to prion-containing aerosols, which induced disease. Exposure to aerosols for one minute was sufficient to induce disease in 100% of mice. The longer the exposure, the shorter the incubation time in the recipient mice, after which they developed the clinical signs of a prion disease. These findings indicate that prions are not airborne. Prions appeared to transfer from the airways and colonize the brain directly, since various immune system defects – known from previous experiments to prevent the passage of prions from the gut to the brain – did not prevent infection.

The prion is the infectious agent that caused the epidemic of “mad cow” disease, also termed bovine spongiform encephalopathy (BSE). BSE claimed the life of more than 280,000 cows in the past decades. Transmission of BSE to humans, e.g. by ingestion of food derived from BSE-infected cows, causes variant Creutzfeldt-Jakob disease which is characterized by a progressive and invariably lethal breakdown of brain cells. Consumption of food made from BSE-infected cows has caused the deaths of almost 300 people. The precautionary measures against prion infections in scientific laboratories, abattoirs, and animal feed factories have not typically included stringent protection against aerosols. These new findings suggest that it may be advisable to consider the possibility of airborne prion transmission, and to create regulations aimed at minimizing the prion infection risks to humans and animals.

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice. (2011) PLoS Pathog 7(1): e1001257. doi:10.1371/journal.ppat.1001257
Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrPC, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrPC selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrPSc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.

Related:

• Researchers find new piece of BSE puzzle
• Oral transmission of prions is enhanced by binding to soil
• New forms of bovine spongiform encephalopathy

Chronic wasting disease (CWD) is a prion disease affecting wild and captive deer. Like all mammalian prion diseases, which include Creutzfeldt-Jakob disease (CJD), kuru and variant CJD (vCJD) in humans and bovine spongiform encephalopathy (BSE) in cattle, the central event in CWD infection is the post-translational conversion of the host-encoded, cellular prion protein (PrPC), to an abnormal form called PrPSc. Progressive accumulation of PrPSc in the central nervous system is associated with clinical signs of CWD which includes weight loss, behavioural changes, excessive salivation, difficulty swallowing and ataxia prior to death. International concern over CWD is growing as infected cervids have now been reported in fourteen states in North America, two Canadian provinces and in South Korea. To date, CWD has not been reported in Europe, although surveillance has been limited.

The negative transmission data reported in this paper support the conclusion that the transmission barrier associated with the interaction of human PrP and these CWD prions is greater than that associated with interaction of human PrP and the prion strain causing epizootic BSE in cattle. This is good news from a human health perspective, but further studies will be required to evaluate the transmission properties of distinct deer prion strains as they are characterized.

Chronic wasting disease prions are not transmissible to transgenic mice over-expressing human prion protein. J Gen Virol. Jul 7 2010
Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids, including mule deer, white-tailed deer, Rocky Mountain elk, and moose. CWD-infected cervids have been reported in fourteen US states, two Canadian provinces and in South Korea. The possibility of a zoonotic transmission of CWD prions via diet is of particular concern in North America where hunting of cervids is a popular sport. To investigate the potential public health risks posed by CWD prions, we have investigated whether intracerebral inoculation of brain and spinal cord from CWD-infected mule deer transmits prion infection to transgenic mice over-expressing human prion protein with methionine or valine at polymorphic residue 129. These transgenic mice have been utilised in extensive transmission studies of human and animal prion disease and are susceptible to BSE and vCJD prions, allowing comparison with CWD. Here we show that these mice proved entirely resistant to infection with mule deer CWD prions arguing that the transmission barrier associated with this prion strain/host combination is greater than that observed with classical BSE prions. However, it is possible that CWD may be caused by multiple prion strains; further studies will be required to evaluate the transmission properties of distinct cervid prion strains as they are characterised.

Prion diseases, also known as transmissible spongiform encephalopathies, are infectious fatal neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated form which may contribute to brain damage. In uninfected individuals, normal PrP is anchored to the outer cell membrane by a sugar-phosphate-lipid linker molecule. This report shows that prion infection of mice expressing PrP lacking the anchor can result in a new type of fatal neurodegenerative disease. The disease displays mechanisms of damage to brain cells and brain blood vessels found in Alzheimer’s disease and in familial amyloid brain diseases. In contrast, the typical sponge-like brain damage seen in prion diseases was not observed. These results suggest that presence or absence of PrP membrane anchoring can influence the type of neurodegeneration seen after prion infection. Understanding these interactiions could lead to new therapeutic approaches.

Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring. 2010 PLoS Pathog 6(3): e1000800. doi:10.1371/journal.ppat.1000800

Related:

• Researchers find new piece of BSE puzzle
• Novel mutation linked to mad cow disease
• What the heck are prions for?
• Drugs for treatment of prion infections

BSE, commonly known as mad cow disease, is caused by an infectious and abnormal form of the prion protein that is present on cells within the nervous system, but it is unclear as to what causes the abnormality to occur. Prion diseases are unique in that their infectious nature is not dependent on nucleic acid but is instead attributed to a misfolded protein, the prion protein. This misfolded prion protein is capable of inducing the misfolding of the normal form of the prion protein that is present on the surface of neurons and other cells in the body. However, the site in the cell at which this misfolding occurs and whether other proteins are involved remains controversial. Researchers have addressed these questions by investigating how the normal form of the prion protein is targeted to specialised domains on the plasma membrane termed cholesterol-rich lipid rafts. They showed that targeting is due, in part, to a particular heparin sulfate proteoglycan called glypican-1.

A new treatment route for bovine spongiform encephalopathy (BSE) and its human form Creutzfeldt Jakob disease (CJD) could be a step closer. This new works shows that the presence of Glypican-1 causes the numbers of abnormal prion proteins to rise. This suggests that Glypican-1 acts as a scaffold bringing the two forms of the prion protein together and that this contact causes normal prions to mutate into the infectious form. These findings may have implications for the treatment of both BSE and the human form of the disease, CJD. Although the scientists mainly conducted experiments using cells infected with prions, it is also possible that Glypican-1 is involved in other diseases of the nervous system, although experiments have not shown any link with other neurodegenerative diseases such as Alzheimer’s disease.

Glypican-1 Mediates Both Prion Protein Lipid Raft Association and Disease Isoform Formation. 2009 PLoS Pathog 5(11): e1000666. doi:10.1371/journal.ppat.1000666
In prion diseases, the cellular form of the prion protein, PrPC, undergoes a conformational conversion to the infectious isoform, PrPSc. PrPC associates with lipid rafts through its glycosyl-phosphatidylinositol (GPI) anchor and a region in its N terminal domain which also binds to heparan sulfate proteoglycans (HSPGs). We show that heparin displaces PrPC from rafts and promotes its endocytosis, suggesting that heparin competes with an endogenous raft-resident HSPG for binding to PrPC. We then utilised a transmembrane-anchored form of PrP (PrP-TM), which is targeted to rafts solely by its N-terminal domain, to show that both heparin and phosphatidylinositol-specific phospholipase C can inhibit its association with detergent-resistant rafts, implying that a GPI-anchored HSPG targets PrPC to rafts. Depletion of the major neuronal GPI anchored HSPG, glypican-1, significantly reduced the raft association of PrP-TM and displaced PrPC from rafts, promoting its endocytosis. Glypican-1 and PrPC colocalised on the cell surface and both PrPC and PrPSc co-immunoprecipitated with glypican-1. Critically, treatment of scrapie-infected N2a cells with glypican-1 siRNA significantly reduced PrPSc formation. In contrast, depletion of glypican-1 did not alter the inhibitory effect of PrPC on the b-secretase cleavage of the Alzheimer’s amyloid precursor protein. These data indicate that glypican-1 is a novel cellular cofactor for prion conversion and we propose that it acts as a scaffold facilitating the interaction of PrPC and PrPSc in lipid rafts.

Related:

• Prions and Alzheimers disease
• Novel mutation linked to mad cow disease
• What the heck are prions for?
• Drugs for treatment of prion infections

Prions are transmissible, proteinaceous agents that cause fatal neurodegenerative diseases. In deer elk moose prions cause chronic wasting disease (CWD). The incidence of CWD can be remarkably high both in captive and wild herds and epidemiological data suggest that efficient horizontal transmission drives epidemic dynamics. Although deer can be infected orally and seem to be able to contract CWD from contaminated environments, precisely how and when CWD prions are shed into the environment have not been described. Previous studies have identified CWD prions in saliva, blood, urine, antler velvet, and muscle, lymphoid and other tissues of symptomatic cervids with late-stage disease. These sources of CWD prions may contribute to the spread of CWD, but none explains natural CWD transmission both within and between species in the deer family. To fit observed patterns, a natural CWD transmission mechanism must be effected within biologically realistic limits of the carrier medium, cannot require cannibalism and should be indirect to explain both environmental persistence and spread among multiple host species. Because empirical data and modelling suggested faecal excretion of prions throughout much of the disease course as potentially important to CWD transmission, researchers investigated whether prions are shed in faeces from mule deer during the course of CWD infection.

Asymptomatic deer excrete infectious prions in faeces. 2009 Nature 461: 529-532 doi:10.1038/nature08289
Infectious prion diseases – scrapie of sheep and chronic wasting disease (CWD) of several species in the deer family – are transmitted naturally within affected host populations. Although several possible sources of contagion have been identified in excretions and secretions from symptomatic animals, the biological importance of these sources in sustaining epidemics remains unclear. Here we show that asymptomatic CWD-infected mule deer (Odocoileus hemionus) excrete CWD prions in their faeces long before they develop clinical signs of prion disease. Intracerebral inoculation of irradiated deer faeces into transgenic mice overexpressing cervid prion protein (PrP) revealed infectivity in 14 of 15 faecal samples collected from five deer at 7–11 months before the onset of neurological disease. Although prion concentrations in deer faeces were considerably lower than in brain tissue from the same deer collected at the end of the disease, the estimated total infectious dose excreted in faeces by an infected deer over the disease course may approximate the total contained in a brain. Prolonged faecal prion excretion by infected deer provides a plausible natural mechanism that might explain the high incidence and efficient horizontal transmission of CWD within deer herds, as well as prion transmission among other susceptible cervids.

Why should we care?
Apart from the impact on wildlife, vCJD is a prion infection transmitted from infected cows to humans. People eat deer. Although there is no evidence that the CWN prion causes diseae in humans, this is definitely one to keep an eye on.

Related:

• A General Model of Prion Strains and Their Pathogenicity
• Prions, Proteasomes, and Mad Cows
• Oral transmission of prions is enhanced by binding to soil
• Prions and Cheetah Conservation

In PNAS, Warren Olanowa and Stanley Prusiner ask, Is Parkinson’s disease a prion disorder?
Parkinson’s disease (PD) is an age-related, neurodegenerative disease that affects approximately one million people in the United States. Pathologically, the disease is characterized by a loss of dopamine neurons in the substantia nigra coupled with proteinaceous inclusions in nerve cells and terminals, known as Lewy bodies and Lewy neurites, respectively. PD pathology is also known to affect nondopamine neurons in the upper and lower brainstem, olfactory system, cerebral hemisphere, spinal cord, and autonomic nervous system. The cause of cell death in PD is not known, but proteolytic stress with the accumulation of misfolded proteins has been implicated.

In the current issue of PNAS, Desplats et al demonstrate that nerve cells which overexpress tagged alpha-synuclein can transmit the protein to neural stem cells in both in vitro and in vivo models (Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. 2009 PNAS USA 106:13004–13005). This important study could explain the remarkable finding that human embryonic dopamine nerve cells implanted into the striatum of patients with PD develop PD pathology with loss of dopamine markers and classic Lewy bodies. It also provides insight into how alpha-synuclein pathology might sequentially spread throughout the nervous system in PD.

It is thus possible that PD is a prion disorder resulting from increased production and/or impaired clearance of proteins such as alpha-synuclein, leading to misfolding and the formation of toxic oligomers, aggregates, and cell death. Further, it is possible that alpha-synuclein is a prion protein that can self-aggregate and be transmitted to unaffected cells, thus extending the disease process. While genetic causes represent an obvious source of increased levels of aberrantly folded alpha-synuclein in familial PD cases, a combination of aging, oxidative stress, inflammation, environmental toxins, hereditary factors, and impaired clearance may all feature in varying ways in causing altered metabolism of alpha-synuclein, resulting in the pathogenesis of sporadic PD. This concept suggests that drugs directed toward reducing the formation and/or facilitating the clearance of misfolded alpha-synuclein, so as to arrest or reverse the self-propagation process, might represent a novel therapeutic interventions for the treatment of PD.

Related:

• Stanley Prusiner at the SGM: Prion Biology and Diseases
• What the heck are prions for?
• Drugs for treatment of prion infections
• Alzheimer’s Disease and Prions