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Review
, 95 (23), 13363-83

Prions

Affiliations
Review

Prions

S B Prusiner. Proc Natl Acad Sci U S A.

Abstract

Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc). The normal, cellular PrP (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high beta-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrPSc. Transgenetic studies argue that PrPSc acts as a template upon which PrPC is refolded into a nascent PrPSc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrPSc. While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

Figures

Figure 1
Figure 1
Neuropathologic changes in Swiss mice after inoculation with RML scrapie prions. (a) Hematoxylin and eosin stain of a serial section of the hippocampus shows spongiform degeneration of the neuropil, with vacuoles 10–30 μm in diameter. Brain tissue was immersion fixed in 10% buffered formalin solution after the animals had been sacrificed and was then embedded in paraffin. Py, pyramidal cell layer; SR, stratum radiatum. (b) Glial fibrillary acidic protein (GFAP) immunohistochemistry of a serial section of the hippocampus shows numerous reactive astrocytes. (Bar in b = 50 μm and also applies to a.) Photomicrographs were prepared by Stephen J. DeArmond.
Figure 2
Figure 2
Prion protein isoforms. (A) Western immunoblot of brain homogenates from uninfected (lanes 1 and 2) and prion-infected (lanes 3 and 4) SHa. Samples in lanes 2 and 4 were digested with 50 μg/ml proteinase K for 30 min at 37°C. PrPC in lanes 2 and 4 was completely hydrolyzed under these conditions, whereas approximately 67 amino acids were digested from the NH2 terminus of PrPSc to generate PrP 27–30. After polyacrylamide gel electrophoresis (PAGE) and electrotransfer, the blot was developed with anti-PrP R073 polyclonal rabbit antiserum. Molecular size markers are in kilodaltons (kDa). (B) Bar diagram of SHaPrP, which consists of 254 amino acids. Attached carbohydrate (CHO) and a glycosyl-phosphatidylinositol (GPI) anchor are indicated. After processing of the NH2 and COOH termini, both PrPC and PrPSc consist of 209 residues. After limited proteolysis, the NH2 terminus of PrPSc is truncated to form PrP 27–30, which is composed of approximately 142 amino acids.
Figure 3
Figure 3
Electron micrographs of negatively stained and ImmunoGold-labeled prion proteins. (A) PrPC. (B) PrPSc. Neither PrPC nor PrPSc forms recognizable, ordered polymers. (C) Prion rods composed of PrP 27–30 were negatively stained. The prion rods are indistinguishable from many purified amyloids. (Bar = 100 nm.)
Figure 4
Figure 4
Species variations and mutations of the prion protein gene. (A) Species variations. The x-axis represents the human PrP sequence, with the five octarepeats and H1–H4 regions of putative secondary structure shown as well as the three α-helices A, B, and C and the two β-strands S1 and S2 as determined by NMR. The precise residues corresponding to each region of secondary structure are given in Fig. 5. Vertical bars above the axis indicate the number of species that differ from the human sequence at each position. Below the axis, the length of the bars indicates the number of alternative amino acids at each position in the alignment. (B) Mutations causing inherited human prion disease and polymorphisms in human, mouse, and sheep. Above the line of the human sequence are mutations that cause prion disease. Below the lines are polymorphisms, some but not all of which are known to influence the onset as well as the phenotype of disease. Data were compiled by Paul Bamborough and Fred E. Cohen.
Figure 5
Figure 5
Structures of prion proteins. (A) NMR structure of SHa recombinant (r) PrP(90–231). Presumably, the structure of the α-helical form of rPrP(90–231) resembles that of PrPC. rPrP(90–231) is viewed from the interface where PrPSc is thought to bind to PrPC. The color scheme is as follows: α-helices A (residues 144–157), B (–193), and C (–227) in pink; disulfide between Cys-179 and Cys-214 in yellow; conserved hydrophobic region composed of residues 113–126 in red; loops in gray; residues 129–134 in green encompassing strand S1 and residues 159–165 in blue encompassing strand S2; the arrows span residues 129–131 and 161–163, as these show a closer resemblance to β-sheet (155). (B) NMR structure of rPrP(90–231) is viewed from the interface where protein X is thought to bind to PrPC. Protein X appears to bind to the side chains of residues that form a discontinuous epitope: some amino acids are in the loop composed of residues 165–171 and at the end of helix B (Gln-168 and Gln-172 with a low-density van der Waals rendering), whereas others are on the surface of helix C (Thr-215 and Gln-219 with a high-density van der Waals rendering) (178). (C) PrP residues governing the transmission of prions (180). NMR structure of recombinant SHaPrP region 121–231 (155) shown with the putative epitope formed by residues 184, 186, 203, and 205 highlighted in red. Residue numbers correspond to SHaPrP. Additional residues (138, 139, 143, 145, 148, and 155) that might participate in controlling the transmission of prions across species are depicted in green. Residues 168, 172, 215, and 219 that form the epitope for the binding of protein X are shown in blue. The three helices (A, B, and C) are highlighted in pink. (D) Schematic diagram showing the flexibility of the polypeptide chain for PrP(29–231) (156). The structure of the portion of the protein representing residues 90–231 was taken from the coordinates of PrP(90–231) (155). The remainder of the sequence was hand-built for illustration purposes only. The color scale corresponds to the heteronuclear {1H}-15N nuclear Overhauser enhancement data: red for the lowest (most negative) values, where the polypeptide is most flexible, to blue for the highest (most positive) values in the most structured and rigid regions of the protein. (E) Plausible model for the tertiary structure of HuPrPSc (166). Color scheme is as follows: S1 β-strands are 108–113 and 116–122 in red; S2 β-strands are 128–135 and 138–144 in green; α-helices H3 (residues 178–191) and H4 (residues 202–218) in gray; loop (residues 142–177) in yellow. Four residues implicated in the species barrier are shown in ball-and-stick form (Asn-108, Met-112, Met-129, Ala-133).
Figure 6
Figure 6
Miniprions produced by deleting PrP residues 23–89 and 141–176. The deletion of residues 141–176 (green) containing helix A and the S2 β-strand is shown. Side chains of residues 168, 172, 215, and 219, which are thought to bind protein X, are shown in cyan.
Figure 7
Figure 7
Tg(PrP106)Prnp0/0 mice were inoculated with RML106 prions containing PrPSc106. Sections of the hippocampus were stained with hematoxylin and eosin (A and C) and immunostained for GFAP (B and D). (A and B) Control Tg(PrP106)Prnp0/0 mouse uninoculated and without neurologic deficits. (C and D) Tg(PrP106)Prnp0/0 mouse inoculated with RML106 prions and sacrificed after signs of neurologic dysfunction were observed. (Bar = 50 μm.) Photomicrographs prepared by Stephen J. DeArmond.
Figure 8
Figure 8
Disappearance of the kuru and BSE epidemics. (A) Annual number of cases of BSE in cattle in Great Britain. (B) Biannual number of cases of kuru in Papua New Guinea. Data were compiled for BSE by John Wilesmith and for kuru by Michael Alpers.
Figure 9
Figure 9
Regional distribution of PrPSc deposition in Tg(MHu2M)Prnp0/0 mice inoculated with prions from humans who died of inherited prion diseases (Table 5). Histoblot of PrPSc deposition in a coronal section a Tg(MHu2M)Prnp0/0 mouse through the hippocampus and thalamus (27). (A) The Tg mouse was inoculated with brain extract prepared from a patient who died of FFI. (B) The Tg mouse was inoculated with extract from a patient with fCJD(E200K). Cryostat sections were mounted on nitrocellulose and treated with proteinase K to eliminate PrPC (209). To enhance the antigenicity of PrPSc, the histoblots were exposed to 3 M guanidinium isothiocyanate before immunostaining using anti-PrP 3F4 mAb (174). (C) Labeled diagram of a coronal sections of the hippocampus/thalamus region. NC, neocortex; Hp, hippocampus; Hb, habenula; Th, thalamus; vpl, ventral posterior lateral thalamic nucleus; Hy, hypothalamus; Am, amygdala. Photomicrographs were prepared by Stephen J. DeArmond.
Figure 10
Figure 10
Histopathology of vCJD in Great Britain. (a) Section from frontal cortex stained by the periodic acid–Schiff method, showing a field with aggregates of plaques surrounded by spongiform degeneration. (×93.) (b) Multiple plaques and amorphous deposits are PrP immunopositive. (×460.) Specimens were provided by James Ironside, Jeanne Bell, and Robert Will; photomicrographs were prepared by Stephen J. DeArmond.

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