Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Aug;68(2):162-72.
doi: 10.1002/ana.22094.

Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein

Wen-Quan Zou  1 , Gianfranco Puoti, Xiangzhu Xiao, Jue Yuan, Liuting Qing, Ignazio Cali, Miyuki Shimoji, Jan P M Langeveld, Rudy Castellani, Silvio Notari, Barbara Crain, Robert E Schmidt, Michael Geschwind, Stephen J Dearmond, Nigel J Cairns, Dennis Dickson, Lawrence Honig, Juan Maria Torres, James Mastrianni, Sabina Capellari, Giorgio Giaccone, Ermias D Belay, Lawrence B Schonberger, Mark Cohen, George Perry, Qingzhong Kong, Piero Parchi, Fabrizio Tagliavini, Pierluigi Gambetti
Affiliations

Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein

Wen-Quan Zou et al. Ann Neurol. 2010 Aug.

Abstract

Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV).

Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics.

Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region.

Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.

PubMed Disclaimer

Conflict of interest statement

Potential Conflicts of Interest

Nothing to report.

Figures

FIGURE 1
FIGURE 1
Histopathology with vacuole size and lesion profiles in the cases belonging to the 3 129 genotypes of variably protease-sensitive prionopathy (VPSPr). The spongiform degeneration is qualitatively similar in all 3 129 genotypes (A, 129VV; B, 129MV; C, 129MM). (D) As originally shown in the 129VV cases, the spongiform degeneration is made of a significant percentage of relatively large and midsize vacuoles on average significantly larger than those of common sporadic Creutzfeldt-Jakob disease (sCJD) subtypes (diameters: VPSPr [combined] 9.3 ± 3.4µ vs sCJDMM1 5.8 ± 1.2µ; p < 0.0001 [Student t test]), resulting in an elongated vacuole size distribution in the vacuole size histogram. (E) The lesion profiles are very similar in the 3 129 genotypes, but show less severe lesions in the 129MM genotype than in the 129VV and 129MV genotypes. FC, TC, PC, and OC = frontal, temporal, parietal, and occipital cortices; HI = CA1 of hippocampus; EC = entorhinal cortex; BG = basal ganglia; TH = thalamus (medial-dorsal nucleus); ST/MB = striatum/midbrain; LC = pons (locus coeruleus); CE = cerebellar cortex. The vertical bars refer to standard deviations. Spongiform degeneration was scored on a 0 to 4 scale (0, not detectable; 1, mild; 2, moderate; 3, severe; and 4, confluent), and astrogliosis on a 0 to 3 scale (0, not detectable; 1, mild; 2, moderate, and 3, severe). (F, G) Homogeneous micro deposits with the appearance of plaques were observed in the molecular layer of the cerebellum in some cases associated with the 129VV (F) and 129MV (G) genotypes, but not in the 3 129MM cases. (A–C, F, G) Hematoxylin & eosin. M = methionine; V = valine.
FIGURE 2
FIGURE 2
Prion protein immunohistochemistry in the 3 variably protease-sensitive prionopathy 129 genotypes. The cerebral cortex (A, C, E) and cerebellar molecular layer (B, D, F) best exemplify the predominant immunostaining patterns. (A) pattern in the 129VV genotype is often targetlike, with a larger stained granule or clusters of granules surrounded by smaller granules in a focal or more diffuse background of punctate or synaptic staining (inset: higher magnification of the same cortical region). (B) The molecular layer of the cerebellum shows relatively large granules that are often compact and intensely stained. (C) In the 129MV genotype, the targetlike pattern is generally less obvious, as large granules are more often isolated; focal or larger areas of synaptic staining are also present (inset: as above). (D) In the cerebellum, the granules are fewer, more loose, and have a plaquelike appearance. (E) The 129MM genotype often shows a plaquelike immunostaining pattern (inset: as above). (F) The cerebellum shows small formations. Immunostaining was done with monoclonal antibody 3F4. M methionine; V = valine.
FIGURE 3
FIGURE 3
Electrophoretic profiles and proteinase K (PK) titration of PK-resistant disease-associated prion protein (PrPDis) from variably protease-sensitive prionopathy (VPSPr) associated with the 129VV, 129MM, or 129MV genotype. (A) The Western blots of the total brain homogenates (BHs) treated with 25µg/ml of PK and probed with the monoclonal antibody 1E4 reveal 5 PrP bands migrating approximately to 26kDa, 23kDa, 20kDa, 17kDa, and 7kDa, forming a ladderlike pattern in all 3 (129VV, 129MM, and 129MV) genotypes of VPSPr (VPSPr26, VPSPr23, VPSPr20, VPSPr17, and VPSPr7) (lanes 1–3). The faint band that migrates at approximately 30kDa in VPSPr-129VV (lane 1) likely represents the incomplete PK digestion of the normal diglycosylated, N-terminus truncated PrP fragment or associated monoglycosylated full-length PrP. In contrast, BHs from sporadic Creutzfeldt-Jakob disease (sCJD) associated with the 129MM genotype and the PrPDis type 1 (sCJDMM1) or sCJDVV2 (sCJD with the 129VV genotype and PrPDis type 2) show the typical 3 PK-resistant PrP fragments of type 1 and 2 migrating between 31kDa and 19kDa (lanes 4 and 5). (B, C) PK titration of PrPDis. Brain homogenates from 129VV, 129MM, and 129MV genotypes were treated with PK at various concentrations between 0 and 100µg/ml. (B) Probed with 1E4. (C) Probed with 3F4. (D) PK titration with quantitative analysis of the individual VPSPr fragments. The curves represent the relative amounts of the individual VPSPr fragments at increasing PK concentrations (0–100µg/ml) after probing the immunoblots with 1E4 in each of the 3 129 genotypes. The relative representations of the bands corresponding to the VPSPr fragments were determined by densitometry and expressed as averages of 129VV (n = 3), 129MM (n = 2), and 129MV cases (n = 3). Comparative analysis of the curves from each of the 3 129 genotypes confirms the PK sensitivity of all the fragments in 129VV cases, with the exception of VPSPr7, which is resistant to PK in all 3 genotypes. The remaining 4 fragments follow similar patterns in both the 129MM and 129MV genotypes; VPSPr26 and VPSPr20 form rapidly but are digested at PK concentrations >10µg/ml; VPSPr23 and VPSPr17 are resistant up to 100µg/ml of PK (*p < 0.02; **p < 0.005). M = methionine; V = valine.
FIGURE 4
FIGURE 4
Proteinase K (PK)-resistant core fragments of variably protease-sensitive prionopathy (VPSPr) and their comparison with the disease-associated prion protein (PrPDis) fragments associated with Gerstmann-Sträussler-Scheinker disease (GSS)-A117V. All brain homogenates were treated with increasing concentrations of PK and with peptide N-glycosidase F (PNGase F). (A) With 1E4, all immunoblots from cases with the 129VV, 129MM, and 129MV genotypes essentially show variably protease-sensitive prionopathy (VPSPr)-20, VPSPr17, and VPSPr7. However, the PK resistance of these bands varies according to the 129 genotype and the individual bands within the same genotype in a way roughly similar to that shown in Figure 3. (B) The immunoblots probed with 3F4 reveal 2 major bands in the 129MM and 129MV genotypes, which, however, exhibit a quite different pattern of resistance to PK in the 2 genotypes. As expected, no PK-resistant PrP bands are detected in the 129VV genotype. (C) Additional analysis of the core fragments following treatment with 25µg/ml of PK and PNGase, using the antibody anti-C to the PrP C-terminal residues 220–231. Compared to 1E4, anti-C demonstrates 4 bands of 20kDa, 18kDa, 12–13kDa, and 8kDa, respectively, of which only the 20kDa band has the same gel mobility as VPSPr20 detected with 1E4. The other 3 bands, including 18kDa, 12–13kDa, and 8kDa, do not match the bands detected with 1E4. (See text for explanation). (D) Brain homogenates from VPSPr-129MV, GSS117, and VPSPr-129 were treated with PK and PNGase F prior to Western blotting and probed with 1E4 (left panel), 3F4 (middle panel), and anti-C (right panel) antibodies. With monoclonal antibody 1E4, bands matching VPSPr20, VPSPr17, and VPSPr7 are detected in the GSS-A117V preparations, but the GSS-V117V bands immunoreact much less with 1E4 than the bands of VPSPr-129MV and VPSPr-129VV. The 23kDa band is seen more prominently in GSS-A117V. With 3F4, the VPSPr17 and VPSPr7 bands are shared by GSS-A117V and VPSPr-129MV, but the 20kDa band is missing in GSS-A117V. The VPSPr7 band is much less reactive in 129MV. As previously, the 129VV is not reactive with 3F4. Anti-C reveals apparently the same bands in all 3 preparations, but with significantly different ratios. M = methionine; V = valine.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gambetti P, Kong Q, Zou WQ, et al. Sporadic and familial CJD: classification and characterization. Br Med Bull. 2003;66:213–239. - PubMed
    1. Prusiner S. Prions. Proc Natl Acad Sci U S A. 1998;95:13363–13383. - PMC - PubMed
    1. Gambetti P, Dong Z, Yuan J, et al. A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol. 2008;63:677–708. - PMC - PubMed
    1. Jansen C, Head MW, van Gool WA, et al. The first case of protease-sensitive prionopathy (PSPr) in The Netherlands: a patient with an unusual GSS-like clinical phenotype. J Neurol Neurosurg Psychiatry. 2010 Jun 14; [Epub ahead of print] - PubMed
    1. Head MW, Knight R, Zeidler M, et al. A case of protease sensitive prionopathy in a patient in the UK. Neuropathol Appl Neurobiol. 2009;35:628–632. - PubMed

Publication types

MeSH terms