An overview of human prion diseases.

Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrP(C). 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 PrP(C) and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Sträussler-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.

[Acquired Creutzfeldt-Jakob disease (CJD)--Kuru, iatrogenic CJD, variant CJD].

Human prion diseases can be classified as sporadic, hereditary or acquired. The acquired forms are known to be caused by the transmission to human from human or animal, via medical appliances, oral intake or parenteral solutions. Usually, peripheral infection such as oral(Kuru) or parenteral (human pituitary hormones) transmission causes cerebellar degenerative form, and central nervous system infection such as neurosurgical treatment, dura mater grafts or corneal grafts transmission causes clinical features similar to sporadic form of Creutzfeldt-Jakob disease (CJD). The variant CJD (vCJD) is considered to be transmitted bovine spongiform encephalopathy(BSE) to human through dietary exposure. The early clinical features of vCJD are dominated by psychiatric symptoms, and minor number of patients have neurological symptoms from the onset. After about 6 months, there are frank neurological signs, including ataxia, cognitive impairment and involuntary movements.

Human and animal spongiform encephalopathies are the result of chronic autoimmune attack in the CNS: a novel medical theory supported by overwhelming experimental evidence.

Spongiform encephalopathies, also called "prion diseases", are fatal degenerative diseases of the central nervous system which can occur in animals (such as the "mad cow disease" in cattle) and also in humans. This paper presents a novel medical theory concerning the pathogenic mechanisms for various human and animal spongiform encephalopathies. It is hypothesized that various forms of prion diseases are essentially autoimmune diseases, resulting from chronic autoimmune attack of the central nervous system. A key step in the pathogenic process leading towards the development of spongiform encephalopathies involves the production of specific autoimmune antibodies against the disease-causing prion protein (PrPsc) and possibly other immunogenic macromolecules present in the brain. As precisely explained in this paper, the autoimmune antibodies produced against PrPsc are responsible for the conversion of the normal cellular prion protein (PrPc) to PrPsc, for the accumulation of PrPsc in the brain and other peripheral tissues, and also for the initiation of an antibody-mediated chronic autoimmune attack of the central nervous system neurons, which would contribute to the development of characteristic pathological changes and clinical symptoms associated with spongiform encephalopathies. The validity and correctness of the proposed theory is supported by an overwhelming body of experimental observations that are scattered in the biomedical literature. In addition, the theory also offers practical new strategies for early diagnosis, treatment, and prevention of various human and animal prion diseases.

Genetic and infectious prion diseases.

Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). Prion diseases include scrapie of sheep and bovine spongiform encephalopathy of cattle as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) of humans. Transgenic (Tg) mice expressing both SHa and mouse (Mo) PrP genes were used to probe the molecular basis of the species barrier and the mechanism of scrapie prion replication. Bioassays of brain extracts from two scrapie-infected Tg lines showed that the prion inoculum determines that prions are synthesized de novo, even though the cells express both PrP genes. Studies with artificial prions produced from chimeric Mo/SHaPrP transgenes underscore the concept that inoculated prion dictates which prion will be replicated. Discovery of mutations in the PrP genes of humans with GSS and familial CJD established that prion diseases are both genetic and infectious. Transgenic mice expressing high levels of MoPrP-P101L, corresponding to the GSS point mutation (P102L) in human PrP, spontaneously develop neurologic dysfunction, spongiform degeneration, and astrocytic gliosis. Inoculation of brain extracts prepared from these Tg (MoPrP-P101L) mice produced neurodegeneration in recipient animals after prolonged incubation times. These results are in accord with those of other studies and argue that prions are devoid of foreign nucleic acid. Structural investigations of cellular prion protein (PrPC) and prion protein scrapie (PrPSc) suggest that the difference may be conformational. Conditions that diminished the beta-sheet content of PrPSc were the same as those identified previously that inactivate prion infectivity. Whether prion diversity as reflected by distinct "strains" producing different patterns of PrPSc accumulation is due to different conformers of PrPSc remains to be established. Advances in the purification and characterization of both PrPC and PrPSc seem to have identified the central event in PrPSc synthesis and prion propagation, ie, the unfolding of PrPC followed by its refolding into PrPSc. These findings underscore the fundamental features of prion structure and propagation that differentiate prions from other transmissible pathogens.

Prion diseases: epidemiology in man.

Prion disease in man was first described as Creutzfeldt-Jacob disease (CJD) in the 1920s. CJD may have three different origins: sporadic, familial, due to mutations in the prion gene, or infectious, due to iatrogenic exposure to infectious brain material. As an example of the latter, kuru, in Papua New Guinea, was a variant of CJD transmitted by cannibalism. Between 1957 and 1982 more than 2500 died of kuru. Sporadic CJD is the most common form of CJD and occurs with an incidence of around one per million in most parts of the world. Familial CJD accounts for approximately 10% of all European cases of CJD, and is associated with inherited mutations of the prion protein gene, caused by one of the 24 single amino acid substitutions or insertions of octapeptide repeats. CJD caused by infections involves either iatrogenic cases of CJD, resulting from exposure to infectious brain, pituitary or ocular tissue, or from ingestion of infected food items. As of today, a few hundred iatrogenic cases of CJD have been diagnosed worldwide, the majority due to transmission by cadaveric pituitary HCG. So far, 111 cases of vCJD have been diagnosed caused by BSE-contaminated food. The size of the epidemic is still unclear and worst-case scenarios indicate that we may expect many thousands of cases in the future.

Neurodegenerative diseases and risk factors: a literature review.

Degenerative diseases of the central nervous system are significant causes of mortality among elderly people in industrialized countries. For the most part, the causes of these diseases are unknown. It is also very difficult to diagnose this type of disease quickly and accurately. This article reviews the epidemiological research on the principal neurodegenerative disorders, focusing on geographical, hereditary and viral and toxicological exposure correlates. We look in particular at the effect of exposure to toxins as well as the effect that deficiencies of elements such as calcium and selenium could have on the development of these neurological diseases. We also consider the possible protectionist effect of some variables on the development of certain neurological diseases.

Slow infections of the central nervous system.

This review describes the recent advances in slow infections of the nervous system emphasizing the pathogenetic aspects of these diseases. A theoretical model for the pathogenesis of subacute sclerosing panencephalitis (SSPE) is proposed, illustrating the factors that may affect host response to the measles virus and allow it to persist and produce the panencephalitis. The isolation of an oncogenic virus from progressive multifocal leukoencephalopathy (PML) has implications in the consideration of a viral etiology for some brain tumors. The agent responsible for the transmissibility of kuru and Creutzfeldt-Jakob disease (CJD) remains uncharacterized despite recent interest in viroids and abnormalities in replication of cell membranes. The epidemiological data on multiple sclerosis suggests an exposure to an infectious agent at an early age of life modified by the host response. No specific agent has been consistently associated with multiple sclerosis. Amyotrophic lateral sclerosis (ALS), Parkinson's disease, Mollaret's meningitis and Behcet's disease are other examples where a virus is suspect but unproven. The ability of viruses to persist in the host for months to years has linked many chronic neurologic diseases to an infectious agent, enlarging the spectrum of disease caused by viruses.

The evolution of views on the nosological position of transmissible spongiform encephalopathies.

We report here on the evolution of view on the nature of transmissible spongiform encephalopathies or prion disease. While the nosological position of these diseases is well understood, the nature of the agent is still a matter of dispute. There is no doubt, however, that the gene for PrP plays a major role in the whole group of neurodegenerations.

Is the pathogen of prion disease a microbial protein?

Though considerable circumstantial evidence suggests that the pathogen of prion disease is proteinaceous, it has not yet been conclusively identified. Epidemiological observations indicate that a microbial vector is responsible for the transmission of natural prion disease in sheep and goats and that the real causative agent may correspond to a structural protein of that microorganism. The microbial protein should resemble prion protein (PrP) and may replicate itself in the host by using mammalian DNA. A similar phenomenon was already described with a protein antigen of the ameba Naegleria gruberi. The various serotypes of the microbial protein may account for the existence of scrapie strains. It is proposed that many microbial proteins may be capable of replicating themselves in mammalian cells eliciting and sustaining thereby degenerative and/or autoimmune reactions subsequent to infections with microorganisms.

[Transmissible spongiform encephalopathies. History, epidemiology, etiological, hyphotheses]. / Le encefalopatie spongiformi trasmissibili. Storia, epidemiologia, ipotesi eziologiche.

The history of transmissible spongiform encephalopathies is shortly reviewed beginning with the Westminster parliament act in the year 1755 up to the description in 1996 of the variant of the Creutzfeldt-Jakob disease, transmitted from cattle to man by alimentary route. The epidemiological patterns of encephalopathies of the various animal species and of the four encephalopathies up to date reported in man are shortly described: Creutzfeldt-Jakob disease, Kuru, Gerstmann-Straussler-Scheinker disease, Fatal Familial Insomnia. Etiological hypotheses are discussed until the identification of Prions: PrPcell, on the surface of normal cells, PrPscr in the brain of humans and animals dead for these diseases. The strains of the PrPscr are described on the basis of some characters observed through the passages in rodents and of molecular pattern. The possible future epidemiological evolution of the vCJD is also discussed.

[Encephalopathy caused by prions]. / Les encéphalopathies dues aux prions.

The concept of prion encephalopathy has emerged from such previous notions as slow virus infections, spongiform encephalopathies or transmissible dementias. The term prion (Prusiner, 1982) is now used in preference to unconventional agents. Proteins and genes of prions have recently been identified by molecular biology. Exactly how prion proteins are amplified in cells is still unknown. It has been demonstrated that amyloid deposits in scrapie-infected brain, Creutzfeldt-Jakob, Gerstmann-Straüssler and Kuru diseases are composed of prion proteins. Prion encephalopathies are good models to study some immunopathological mechanisms observed in the central nervous system in degenerative diseases or ageing.

[Prions, infections and confusions in the "transmissible" spongiform encephalopathies. The other evidence-based science. III. Review]. / Priones, infecciones y confusiones en las encefalopatías espongiformes "trasmisibles". Ciencia basada en la otra evidencia III. Revisión.

There are some neurological disorders with a pathological hallmark called spongiosis which include Creutzfeld-Jakob disease and its new variant, the Gertsmann-Straussler-Scheinker Syndrome and the Fatal Familial Insomnia in humans; and Scrapie and Bovine Spongiform Encephalopathy, among others, in animals. The etiological agent has been considered either transmissible or hereditary or both. Curiously, this agent has no nucleic acids, is impossible to filter, is resistant to inactivation by chemical means, has not been cultured and is unobservable at electron microscopy. All of these facts have led to some researches to claim that these agents are similar to viruses appearing in computers. However, after almost fifty years of research, is still not possible to explain why and how such elements produce the diseases commented about. On the contrary, during these years have been possible to know that these entities called slow viral infections, transmissible amyloidosis, transmissible dementia, transmissible spongiform encephalopathies or prion diseases appear in individuals with genetical predispositions exposed to several worldwide immunological stressors. The possibility that prions are the consequence and not the cause of these diseases in animals and man is day by day more reliable, and supports the suggestion that a systematic intoxication due to pesticides as well as mycotoxin ingestion, produced mainly by different molds such as Aspergillus, Penicillium or Fusarium, seem to be the true etiology of these neurodegenerative disorders.

[Human transmissible subacute spongiform encephalopathy]. / Les encéphalopathies subaiguës spongiformes transmissibles humaines.

Human transmissible spongiform encephalopathies (TSE) are rare chronic subacute degenerative diseases of the central nervous system (CNS) which include Creutzfeldt-Jakob disease (CJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). CJD can be either inherited or sporadic. All these diseases are always fatal. Neuropathological features are mainly constituted of neuronal vacuolisation, neuronal death, gliosis with hyperastrocytosis; plaques might be evidenced in kuru and GSS. Neither inflammatory syndrome nor demyelination is detectable. No virus like structure could be identified reproducibly. Human TSE are transmissible to non human primates and rodents. Iatrogenic CJD have been described after tissue grafting (cornea, dura mater), neurosurgery, electrophysiology investigation, and treatment with pituitary derived gonadotrophins and growth hormone. Molecular biochemistry of the CNS investigation revealed that a host encoded protein, the prion protein (PrP), accumulates proportionally to the infectious titer: this abnormality is the only detectable hallmark in TSE. Infectious fractions contain no detectable specific nucleic acid, and are mainly constituted of PrP under an isoform which resists to proteinase K digestion (PrP-res). The PrP gene (PRNP) is located on chromosome 20 in humans. Several mutations of this gene have been described in all inherited TSE (CJD, GSS, and IFF). No treatment is available today. Agents inducing TSE (TSA) are not known: several authors claim that TSA are only constituted of PrP-res; others support the hypothesis of a conventional agent with a specific genetic information.

[Prion disease and brain amyloidosis]. / Prionovye bolezni i amiloidoz golovnogo mozga.

Human prion disorders include Kuru, Creutzfeld-Jakob disease (CJD), Gerstman-Straussler-Scheinkler syndrome (GSS), fatal familial insomnia (FFI) and prion protein cerebral amyloid angiopathy (PrPCAA). Prion diseases manifest as infections, genetic and sporadic disorders. In these diseases an abnormal form of the host's protein, prion protein protease-resistant (PrPres), is essential for pathogenic process. Host protein, prion protein protease-sensitive (PrPsen) in humans is encoded by a single copy gene (PRNP) located in the short arm of chromosome 20. To date, 19 different mutations in PRNP have been found that cause inherited prion disease. In these diseases PrPsen undergoes conformational changes involving a shift from alpha-helix to beta-sheet structures. This conversion is important for PrP-amyloidogenesis which occurs to the highest degree in GSS, while it is less frequently seen in other prion diseases. Pathomorphologically, amyloidogenesis in the brain is characterized by formation of PrPres conglomerates, diffuse homogeneous deposits and pleomorphic fibrillar amyloid plaques. The neurotoxic activity of PrPres and its fragments supports the causal relationship between PrPres deposits and neuropathological events in prion diseases. Congo-red and certain sulfated glycans potently inhibit PrPres formation. This raises the potential of therapeutic strategies for the treatment of these diseases.