The Prion Diseases
The Prion Diseases
The prion diseases constitute an unusual group of neurodegenerative disorders. Although they are similar in many ways to other more common diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, they are set apart on the basis of their transmissible nature. In addition to the unique feature of transmissibility, the prion diseases demonstrate that the expression of diverse disease phenotypes is possible from a common etiologic factor. This review provides the reader with a basic understanding of the nature of prions and highlights the clinical and pathologic features of these fascinating diseases.
The human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), Gerstmann-Sträussler-Scheinker (GSS) disease, fatal insomnia (FI), and, more recently, new variant CJD (nvCJD or vCJD). In addition to these human diseases, prion-related diseases have been recognized in several animal hosts. Scrapie is a naturally occurring disease of sheep and goats that causes ataxia, behavioral changes, and a severe pruritus that leads to scraping behavior, from which the disease was named. Additional prion diseases in animals include transmissible mink encephalopathy (TME), chronic wasting dis-ease (CWD) of deer and elk, feline spongiform encephalopathy (FSE), and bovine spongiform encephalopathy (BSE), among others. Most of these diseases are presumed to result from ingestion of animal by-products contaminated with sheep scrapie, although CWD appears to be a naturally occurring disease of North America.
The transmissible nature of prion disease was first demonstrated experimentally in 1936 when Cuillé and Chelle transmitted scrapie to a healthy goat by the intraocular administration of scrapie-infected spinal cord. Thirty years later, kuru, a disease transmitted among the Fore people of New Guinea through the ritualistic practice of cannibalism, was experimentally transmitted to chimpanzees by Gajdusek and colleagues. Shortly thereafter, sCJD was transmitted to chimpanzees. The pathologic feature common to all these diseases is a prominent vacuolation of the gray matter of the brain that produces a "spongelike" appearance on light microscopy. This histopathologic appearance, coupled with the transmissible nature of these diseases, led to their collective designation as "transmissible spongiform encephalopathies" or TSEs.
The etiologic agent of the TSEs was proposed to be a "slow virus" by Sigurdsson4 to explain its transmissible nature and the prolonged incubation period observed during experimental transmission studies. Early experiments by Alper et al, however, suggested that protein may be a critical component of the infectious agent. Prusiner pursued this idea and in so doing established the basis for a new form of transmissible pathogen, one that is composed ostensibly of only protein and lacks any replicative elements such as nucleic acid. Although neither the viral nor the protein-only theory has been proved, evidence in favor of the protein-only hypothesis has overwhelmed the virus camp, resulting in a Nobel Prize in Medicine for Prusiner in 1997.
What are prions? The term "prion" was coined by Prusiner to indicate an infectious agent with proteinlike properties. The unusual properties of the pathogen were demonstrated in early experiments in which conditions that degrade nucleic acids, such as exposure to ionizing and ultraviolet radiation, did not reduce the infectivity of scrapie fractions; on the other hand, treatments that degrade protein, such as prolonged exposure to proteases, correlated with a reduction in infectivity. A protein with relative resistance to protease digestion was found to be consistently present in the brains of animals and humans with TSE. Surprisingly, this protein was found to be one that is normally encoded by a chromosomal gene of the host.
How could a normally expressed protein also be a transmissible pathogen? It was hypothesized and later demonstrated that PrP exists in two major isoforms: the nonpathogenic or cellular form, designated PrP, and the pathogenic or scrapie-inducing form, designated PrP. Both PrP and PrP have the same amino acid sequence, yet they differ in their biochemical properties: PrP is soluble in nondenaturing detergents and completely degraded by proteases, whereas PrP is insoluble in nondenaturing detergents and shows a relative resistance to proteases. Structural studies of PrP and PrP indicate a difference in the conformation of the two isoforms: PrP is predominantly -helical, whereas PrP contains at least 40% -pleated sheet structure. Conversion to this -sheet structure appears to be the fundamental event in prion disease. The ultimate mechanism of how cells die coincident with the generation of prions is still unclear. Simple accumulation of pathogenic protein may not be sufficient to explain disease, however, it may constitute a critical step in cellular dysfunction.
How does PrP convert to PrP? Potential mechanisms that initiate conversion of PrP to PrP include a germ line mutation of the human prion protein gene (PRNP), a somatic mutation within a particular neuron, and spontaneous conversion of PrP to an aberrant conformation that is not refolded appropriately to its native structure. Regardless of the initiating event, once an "infectious unit" has been generated, PrP appears to act as a conformational template by which PrP is converted to a new molecule of PrP through protein-protein interaction of PrP and PrP (Fig. 1A,B). This concept is supported by several studies which show that mice with the normal PrP gene deleted (PrP knockout mice) do not develop prion disease after inoculation with scrapie. Furthermore, transgenic (Tg) mice that express a chimeric PrP gene made of human (Hu) and mouse (M) segments, designated Tg(MHu2M), develop protease-resistant chimeric mouse-human PrP (i.e., MHu2MPrP) in their brains when inoculated with brain extracts from humans with prion disease. These findings clearly illustrate that prions do not self-replicate but instead convert nonpathogenic PrP to pathogenic PrP.
(Enlarge Image)
(A) Potential mechanisms by which conversion to PrPSc is initiated. In humans three potential mechanisms are postulated to give rise to PrPSc. A, Germline mutation: The genetic varieties of disease are most easily explained by a mutation of the PRNP gene that acts to destabilize PrP, which in turn leads to the generation of PrPSc. B, Somatic mutation: A mutation may occur within a single cell or group of cells in the brain to induce the disease-causing conformation of PrP. C, PrP may naturally adopt an intermediate unstable form (designated by the star) that can be converted relatively easily to the native state or the pathogenic state. This may depend on factors within the cell that help to stabilize or destabilize PrP. (B) PrPSc acts as a conformational template to generate new PrPSc with a similar conformation. PrPSc appears to acquire several pathogenic conformational subtypes, which may help explain the diverse phenotypes of prion disease. Once PrPSc is generated by any of the mechanisms described in (A) or through an as yet undetermined mechanism, it induces the conversion of nonpathogenic PrPC to PrPSc by interaction of the two protein conformations. In this example, PrPSc is shown in two potential conformations. PrPSc with conformation A generates new PrPSc with conformation A, and PrPSc with conformation B generates new PrPSc with conformation B. This property helps to explain how prion strains with characteristic phenotypic properties are transferred and maintained.
The prion diseases constitute an unusual group of neurodegenerative disorders. Although they are similar in many ways to other more common diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, they are set apart on the basis of their transmissible nature. In addition to the unique feature of transmissibility, the prion diseases demonstrate that the expression of diverse disease phenotypes is possible from a common etiologic factor. This review provides the reader with a basic understanding of the nature of prions and highlights the clinical and pathologic features of these fascinating diseases.
The human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), Gerstmann-Sträussler-Scheinker (GSS) disease, fatal insomnia (FI), and, more recently, new variant CJD (nvCJD or vCJD). In addition to these human diseases, prion-related diseases have been recognized in several animal hosts. Scrapie is a naturally occurring disease of sheep and goats that causes ataxia, behavioral changes, and a severe pruritus that leads to scraping behavior, from which the disease was named. Additional prion diseases in animals include transmissible mink encephalopathy (TME), chronic wasting dis-ease (CWD) of deer and elk, feline spongiform encephalopathy (FSE), and bovine spongiform encephalopathy (BSE), among others. Most of these diseases are presumed to result from ingestion of animal by-products contaminated with sheep scrapie, although CWD appears to be a naturally occurring disease of North America.
The transmissible nature of prion disease was first demonstrated experimentally in 1936 when Cuillé and Chelle transmitted scrapie to a healthy goat by the intraocular administration of scrapie-infected spinal cord. Thirty years later, kuru, a disease transmitted among the Fore people of New Guinea through the ritualistic practice of cannibalism, was experimentally transmitted to chimpanzees by Gajdusek and colleagues. Shortly thereafter, sCJD was transmitted to chimpanzees. The pathologic feature common to all these diseases is a prominent vacuolation of the gray matter of the brain that produces a "spongelike" appearance on light microscopy. This histopathologic appearance, coupled with the transmissible nature of these diseases, led to their collective designation as "transmissible spongiform encephalopathies" or TSEs.
The etiologic agent of the TSEs was proposed to be a "slow virus" by Sigurdsson4 to explain its transmissible nature and the prolonged incubation period observed during experimental transmission studies. Early experiments by Alper et al, however, suggested that protein may be a critical component of the infectious agent. Prusiner pursued this idea and in so doing established the basis for a new form of transmissible pathogen, one that is composed ostensibly of only protein and lacks any replicative elements such as nucleic acid. Although neither the viral nor the protein-only theory has been proved, evidence in favor of the protein-only hypothesis has overwhelmed the virus camp, resulting in a Nobel Prize in Medicine for Prusiner in 1997.
What are prions? The term "prion" was coined by Prusiner to indicate an infectious agent with proteinlike properties. The unusual properties of the pathogen were demonstrated in early experiments in which conditions that degrade nucleic acids, such as exposure to ionizing and ultraviolet radiation, did not reduce the infectivity of scrapie fractions; on the other hand, treatments that degrade protein, such as prolonged exposure to proteases, correlated with a reduction in infectivity. A protein with relative resistance to protease digestion was found to be consistently present in the brains of animals and humans with TSE. Surprisingly, this protein was found to be one that is normally encoded by a chromosomal gene of the host.
How could a normally expressed protein also be a transmissible pathogen? It was hypothesized and later demonstrated that PrP exists in two major isoforms: the nonpathogenic or cellular form, designated PrP, and the pathogenic or scrapie-inducing form, designated PrP. Both PrP and PrP have the same amino acid sequence, yet they differ in their biochemical properties: PrP is soluble in nondenaturing detergents and completely degraded by proteases, whereas PrP is insoluble in nondenaturing detergents and shows a relative resistance to proteases. Structural studies of PrP and PrP indicate a difference in the conformation of the two isoforms: PrP is predominantly -helical, whereas PrP contains at least 40% -pleated sheet structure. Conversion to this -sheet structure appears to be the fundamental event in prion disease. The ultimate mechanism of how cells die coincident with the generation of prions is still unclear. Simple accumulation of pathogenic protein may not be sufficient to explain disease, however, it may constitute a critical step in cellular dysfunction.
How does PrP convert to PrP? Potential mechanisms that initiate conversion of PrP to PrP include a germ line mutation of the human prion protein gene (PRNP), a somatic mutation within a particular neuron, and spontaneous conversion of PrP to an aberrant conformation that is not refolded appropriately to its native structure. Regardless of the initiating event, once an "infectious unit" has been generated, PrP appears to act as a conformational template by which PrP is converted to a new molecule of PrP through protein-protein interaction of PrP and PrP (Fig. 1A,B). This concept is supported by several studies which show that mice with the normal PrP gene deleted (PrP knockout mice) do not develop prion disease after inoculation with scrapie. Furthermore, transgenic (Tg) mice that express a chimeric PrP gene made of human (Hu) and mouse (M) segments, designated Tg(MHu2M), develop protease-resistant chimeric mouse-human PrP (i.e., MHu2MPrP) in their brains when inoculated with brain extracts from humans with prion disease. These findings clearly illustrate that prions do not self-replicate but instead convert nonpathogenic PrP to pathogenic PrP.
(Enlarge Image)
(A) Potential mechanisms by which conversion to PrPSc is initiated. In humans three potential mechanisms are postulated to give rise to PrPSc. A, Germline mutation: The genetic varieties of disease are most easily explained by a mutation of the PRNP gene that acts to destabilize PrP, which in turn leads to the generation of PrPSc. B, Somatic mutation: A mutation may occur within a single cell or group of cells in the brain to induce the disease-causing conformation of PrP. C, PrP may naturally adopt an intermediate unstable form (designated by the star) that can be converted relatively easily to the native state or the pathogenic state. This may depend on factors within the cell that help to stabilize or destabilize PrP. (B) PrPSc acts as a conformational template to generate new PrPSc with a similar conformation. PrPSc appears to acquire several pathogenic conformational subtypes, which may help explain the diverse phenotypes of prion disease. Once PrPSc is generated by any of the mechanisms described in (A) or through an as yet undetermined mechanism, it induces the conversion of nonpathogenic PrPC to PrPSc by interaction of the two protein conformations. In this example, PrPSc is shown in two potential conformations. PrPSc with conformation A generates new PrPSc with conformation A, and PrPSc with conformation B generates new PrPSc with conformation B. This property helps to explain how prion strains with characteristic phenotypic properties are transferred and maintained.
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