Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2013

Open Access 01-12-2013 | Research

Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein

Authors: Atsushi Kobayashi, Yasushi Iwasaki, Hiroyuki Otsuka, Masahito Yamada, Mari Yoshida, Yuichi Matsuura, Shirou Mohri, Tetsuyuki Kitamoto

Published in: Acta Neuropathologica Communications | Issue 1/2013

Login to get access

Abstract

Background

Sporadic Creutzfeldt-Jakob disease is classified according to the genotype at polymorphic codon 129 (M or V) of the prion protein (PrP) gene and the type (1 or 2) of abnormal isoform of PrP (PrPSc) in the brain. The most complicated entity in the current classification system is MV2, since it shows wide phenotypic variations, i.e., MV2 cortical form (MV2C), MV2 with kuru plaques (MV2K), or a mixed form (MV2K + C). To resolve their complicated pathogenesis, we performed a comprehensive analysis of the three MV2 subgroups based on histopathological, molecular, and transmission properties.

Results

In histopathological and molecular analyses, MV2C showed close similarity to MM2 cortical form (MM2C) and could be easily discriminated from the other MV2 subgroups. By contrast, MV2K and MV2K + C showed the same molecular type and the same transmission type, and the sole difference between MV2K and MV2K + C was the presence of cortical pathology characteristic of MV2C/MM2C. The remarkable molecular feature of MV2K or MV2K + C was a mixture of type 2 PrPSc and intermediate type PrPSc, which shows intermediate electrophoretic mobility between types 1 and 2 PrPSc. Modeling experiments using PrP-humanized mice indicated that MV2K contains a mixture of intermediate type PrPSc with the 129M genotype (Mi PrPSc) and type 2 PrPSc with the 129V genotype (V2 PrPSc) that originated from V2 PrPSc, whereas MV2C + K may also contain type 2 PrPSc with the 129M genotype and cortical pathology (M2C PrPSc) that lacks infectivity to the PrP-humanized mice in addition to Mi and V2 PrPSc.

Conclusions

Taken together, the present study suggests that the phenotypic heterogeneity of MV2 stems from their different PrPSc origin(s).
Appendix
Available only for authorised users
Literature
1.
2.
Parchi P, Castellani R, Capellari S, Ghetti B, Young K, Chen SG, et al.: Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 1996, 39: 767–778.CrossRefPubMed
3.
Parchi P, Capellari S, Chen SG, Petersen RB, Gambetti P, Kopp N, et al.: Typing prion isoforms. Nature 1997, 386: 232–234.CrossRefPubMed
4.
Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al.: Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999, 46: 224–233.CrossRefPubMed
5.
Parchi P, Strammiello R, Giese A, Kretzschmar H: Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathol 2011, 121: 91–112.CrossRefPubMed
6.
Parchi P, Zou W, Wang W, Brown P, Capellari S, Ghetti B, et al.: Genetic influence on the structural variations of the abnormal prion protein. Proc Natl Acad Sci USA 2000, 97: 10168–10172.PubMedCentralCrossRefPubMed
7.
Collinge J, Sidle KC, Meads J, Ironside J, Hill AF: Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 1996, 383: 685–690.CrossRefPubMed
8.
Hill AF, Joiner S, Wadsworth JD, Sidle KC, Bell JE, Budka H, et al.: Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 2003, 126: 1333–1346.CrossRefPubMed
9.
Parchi P, Strammiello R, Notari S, Giese A, Langeveld JP, Ladogana A, et al.: Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrP Sc types: an updated classification. Acta Neuropathol 2009, 118: 659–671.PubMedCentralCrossRefPubMed
10.
Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I, Gambetti P, et al.: Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 2012, 124: 517–529.PubMedCentralCrossRefPubMed
11.
Notari S, Capellari S, Giese A, Westner I, Baruzzi A, Ghetti B, et al.: Effects of different experimental conditions on the PrP Sc core generated by protease digestion. J Biol Chem 2004, 279: 16797–16804.CrossRefPubMed
12.
Notari S, Capellari S, Langeveld J, Giese A, Strammiello R, Gambetti P, et al.: A refined method for molecular typing reveals that co-occurrence of PrP Sc types in Creutzfeldt-Jakob disease is not the rule. Lab Invest 2007, 87: 1103–1112.CrossRefPubMed
13.
Bishop MT, Will RG, Manson JC: Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties. Proc Natl Acad Sci USA 2010, 107: 12005–12010.PubMedCentralCrossRefPubMed
14.
Kitamoto T, Shin R-W, Doh-ura K, Tomokane N, Miyazono M, Muramoto T, et al.: Abnormal isoform of prion proteins accumulates in the synaptic structures of the central nervous system in patients with Creutzfeldt-Jakob disease. Am J Pathol 1992, 140: 1285–1294.PubMedCentralPubMed
15.
Taguchi Y, Mohri S, Ironside JW, Muramoto T, Kitamoto T: Humanized knock-in mice expressing chimeric prion protein showed varied susceptibility to different human prions. Am J Pathol 2003, 163: 2585–2593.PubMedCentralCrossRefPubMed
16.
Kitamoto T, Ohta M, Doh-ura K, Hitoshi S, Terao Y, Tateishi J: Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. Biochem Biophys Res Commun 1993, 191: 709–714.CrossRefPubMed
17.
Kitamoto T, Mohri S, Ironside JW, Miyoshi I, Tanaka T, Kitamoto N, et al.: Follicular dendritic cell of the knock-in mouse provides a new bioassay for human prions. Biochem Biophys Res Commun 2002, 294: 280–286.CrossRefPubMed
18.
Asano M, Mohri S, Ironside JW, Ito M, Tamaoki N, Kitamoto T: vCJD prion acquires altered virulence through trans-species infection. Biochem Biophys Res Commun 2006, 342: 293–299.CrossRefPubMed
19.
Kascsak RJ, Rubenstein R, Merz PA, Tonna-DeMasi M, Fersko R, Carp RI, et al.: Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 1987, 61: 3688–3693.PubMedCentralPubMed
20.
Muramoto T, Tanaka T, Kitamoto N, Sano C, Hayashi Y, Kutomi T, et al.: Analyses of Gerstmann-Straussler syndrome with 102Leu219Lys using monoclonal antibodies that specifically detect human prion protein with 219Glu. Neurosci Lett 2000, 288: 179–182.CrossRefPubMed
21.
Satoh K, Muramoto T, Tanaka T, Kitamoto N, Ironside JW, Nagashima K, et al.: Association of an 11–12 kDa protease-resistant prion protein fragment with subtypes of dura graft-associated Creutzfeldt-Jakob disease and other prion diseases. J Gen Virol 2003, 84: 2885–2893.CrossRefPubMed
22.
Kitamoto T, Muramoto T, Hilbich C, Beyreuther K, Tateishi J: N-terminal sequence of prion protein is also integrated into kuru plaques in patients with Gerstmann-Sträussler syndrome. Brain Res 1991, 545: 319–321.CrossRefPubMed
23.
Grathwohl KUD, Horiuchi M, Ishiguro N, Shinagawa M: Improvement of PrP Sc -detection in mouse spleen early at the preclinical stage of scrapie with collagenase-completed tissue homogenization and Sarkosyl-NaCl extraction of PrP Sc . Arch Virol 1996, 141: 1863–1874.CrossRefPubMed
24.
Ikeda S, Kobayashi A, Kitamoto T: Thr but Asn of the N-glycosylation sites of PrP is indispensable for its misfolding. Biochem Biophys Res Commun 2008, 369: 1195–1198.CrossRefPubMed
25.
Kobayashi A, Sakuma N, Matsuura Y, Mohri S, Aguzzi A, Kitamoto T: Experimental verification of a traceback phenomenon in prion infection. J Virol 2010, 84: 3230–3238.PubMedCentralCrossRefPubMed
26.
Polymenidou M, Stoeck K, Glatzel M, Vey M, Bellon A, Aguzzi A: Coexistence of multiple PrP Sc types in individuals with Creutzfeldt-Jakob disease. Lancet Neurol 2005, 4: 805–814.CrossRefPubMed
27.
Yull HM, Ritchie DL, Langeveld JP, van Zijderveld FG, Bruce ME, Ironside JW, et al.: Detection of type 1 prion protein in variant Creutzfeldt-Jakob disease. Am J Pathol 2006, 168: 151–157.PubMedCentralCrossRefPubMed
28.
Kobayashi A, Mizukoshi K, Iwasaki Y, Miyata H, Yoshida Y, Kitamoto T: Co-occurrence of types 1 and 2 PrP res in sporadic Creutzfeldt-Jakob disease MM1. Am J Pathol 2011, 178: 1309–1315.PubMedCentralCrossRefPubMed
29.
Kobayashi A, Asano M, Mohri S, Kitamoto T: Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a new prion strain. J Biol Chem 2007, 282: 30022–30028.CrossRefPubMed
30.
Paxinos G, Franklin KBJ: The mouse brain in stereotaxic coordinates. 4th edition. London: Academic Press; 2012.
31.
Kobayashi A, Asano M, Mohri S, Kitamoto T: A traceback phenomenon can reveal the origin of prion infection. Neuropathology 2009, 29: 619–624.CrossRefPubMed
32.
Kretzschmar HA, Sethi S, Földvári Z, Windl O, Querner V, Zerr I, et al.: Iatrogenic Creutzfeldt-Jakob disease with florid plaques. Brain Pathol 2003, 13: 245–249.CrossRefPubMed
33.
34.
Hizume M, Kobayashi A, Teruya K, Ohashi H, Ironside JW, Mohri S, et al.: Human prion protein (PrP) 219K is converted to PrP Sc but shows heterozygous inhibition in variant Creutzfeldt-Jakob disease infection . J Biol Chem 2009, 284: 3603–3609.CrossRefPubMed
35.
36.
Parchi P, Cescatti M, Notari S, Schulz-Schaeffer WJ, Capellari S, Giese A, et al.: Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease . Brain 2010, 133: 3030–3042.PubMedCentralCrossRefPubMed
37.
Yamada M, Noguchi-Shinohara M, Hamaguchi T, Nozaki I, Kitamoto T, Sato T, et al.: Dura mater graft-associated Creutzfeldt-Jakob disease in Japan: clinicopathological and molecular characterization of the two distinct subtypes. Neuropathology 2009, 29: 609–618.CrossRefPubMed
Metadata
Title
Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein
Authors
Atsushi Kobayashi
Yasushi Iwasaki
Hiroyuki Otsuka
Masahito Yamada
Mari Yoshida
Yuichi Matsuura
Shirou Mohri
Tetsuyuki Kitamoto
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2013
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/2051-5960-1-74

Other articles of this Issue 1/2013

Acta Neuropathologica Communications 1/2013 Go to the issue

Research

Identification of a neuronal transcription factor network involved in medulloblastoma development

Research

Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?

Research

Focal cortical dysplasias in autism spectrum disorders

Review

The airbag problem–a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer’s disease

Research

Blast overpressure induces shear-related injuries in the brain of rats exposed to a mild traumatic brain injury

Research

Myositis facilitates preclinical accumulation of pathological prion protein in muscle