Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease

The methionine (M)-valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion...

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Autores: Gelpi, Ellen, Baiardi, Simone, Nos, Carlos, Dellavalle, Sofia, Aldecoa, Iban, Ruiz Garcia, Raquel, Ispierto, Lourdes, Escudero, Domingo, Casado, Virgina, Barranco, Elena, Boltes, Anuncia, Molina Porcel, Laura, Bargalló Alabart, Núria, Rossi, Marcello, Mammana, Angela, Tiple, Dorina, Vaianella, Luana, Stoegmann, Elisabeth, Simonitsch-Klupp, Ingrid, Kasprian, Gregor, Klotz, Sigrid, Höftberger, Romana, Budka, Herbert, Kovacs, Gabor G., Ferrer, Isidro (Ferrer Abizanda), Capellari, Sabina, Sánchez Valle, Raquel, Parchi, Piero
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/188966
Acesso em linha:https://hdl.handle.net/2445/188966
Access Level:acceso abierto
Palavra-chave:Malalties per prions
Malaltia de Creutzfeldt-Jakob
Prion diseases
Creutzfeldt-Jakob disease
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spelling Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion diseaseGelpi, EllenBaiardi, SimoneNos, CarlosDellavalle, SofiaAldecoa, IbanRuiz Garcia, RaquelIspierto, LourdesEscudero, DomingoCasado, VirginaBarranco, ElenaBoltes, AnunciaMolina Porcel, LauraBargalló Alabart, NúriaRossi, MarcelloMammana, AngelaTiple, DorinaVaianella, LuanaStoegmann, ElisabethSimonitsch-Klupp, IngridKasprian, GregorKlotz, SigridHöftberger, RomanaBudka, HerbertKovacs, Gabor G.Ferrer, Isidro (Ferrer Abizanda)Capellari, SabinaSánchez Valle, RaquelParchi, PieroMalalties per prionsMalaltia de Creutzfeldt-JakobPrion diseasesCreutzfeldt-Jakob diseaseThe methionine (M)-valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype.Springer Science and Business Media LLC2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/188966Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s40478-022-01415-7Acta Neuropathologica Communications, 2022, vol. 10, núm. 1https://doi.org/10.1186/s40478-022-01415-7cc by (c) Gelpi, Ellen et al., 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1889662026-05-27T06:46:51Z
dc.title.none.fl_str_mv Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
title Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
spellingShingle Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
Gelpi, Ellen
Malalties per prions
Malaltia de Creutzfeldt-Jakob
Prion diseases
Creutzfeldt-Jakob disease
title_short Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
title_full Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
title_fullStr Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
title_full_unstemmed Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
title_sort Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease
dc.creator.none.fl_str_mv Gelpi, Ellen
Baiardi, Simone
Nos, Carlos
Dellavalle, Sofia
Aldecoa, Iban
Ruiz Garcia, Raquel
Ispierto, Lourdes
Escudero, Domingo
Casado, Virgina
Barranco, Elena
Boltes, Anuncia
Molina Porcel, Laura
Bargalló Alabart, Núria
Rossi, Marcello
Mammana, Angela
Tiple, Dorina
Vaianella, Luana
Stoegmann, Elisabeth
Simonitsch-Klupp, Ingrid
Kasprian, Gregor
Klotz, Sigrid
Höftberger, Romana
Budka, Herbert
Kovacs, Gabor G.
Ferrer, Isidro (Ferrer Abizanda)
Capellari, Sabina
Sánchez Valle, Raquel
Parchi, Piero
author Gelpi, Ellen
author_facet Gelpi, Ellen
Baiardi, Simone
Nos, Carlos
Dellavalle, Sofia
Aldecoa, Iban
Ruiz Garcia, Raquel
Ispierto, Lourdes
Escudero, Domingo
Casado, Virgina
Barranco, Elena
Boltes, Anuncia
Molina Porcel, Laura
Bargalló Alabart, Núria
Rossi, Marcello
Mammana, Angela
Tiple, Dorina
Vaianella, Luana
Stoegmann, Elisabeth
Simonitsch-Klupp, Ingrid
Kasprian, Gregor
Klotz, Sigrid
Höftberger, Romana
Budka, Herbert
Kovacs, Gabor G.
Ferrer, Isidro (Ferrer Abizanda)
Capellari, Sabina
Sánchez Valle, Raquel
Parchi, Piero
author_role author
author2 Baiardi, Simone
Nos, Carlos
Dellavalle, Sofia
Aldecoa, Iban
Ruiz Garcia, Raquel
Ispierto, Lourdes
Escudero, Domingo
Casado, Virgina
Barranco, Elena
Boltes, Anuncia
Molina Porcel, Laura
Bargalló Alabart, Núria
Rossi, Marcello
Mammana, Angela
Tiple, Dorina
Vaianella, Luana
Stoegmann, Elisabeth
Simonitsch-Klupp, Ingrid
Kasprian, Gregor
Klotz, Sigrid
Höftberger, Romana
Budka, Herbert
Kovacs, Gabor G.
Ferrer, Isidro (Ferrer Abizanda)
Capellari, Sabina
Sánchez Valle, Raquel
Parchi, Piero
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties per prions
Malaltia de Creutzfeldt-Jakob
Prion diseases
Creutzfeldt-Jakob disease
topic Malalties per prions
Malaltia de Creutzfeldt-Jakob
Prion diseases
Creutzfeldt-Jakob disease
description The methionine (M)-valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/188966
url https://hdl.handle.net/2445/188966
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s40478-022-01415-7
Acta Neuropathologica Communications, 2022, vol. 10, núm. 1
https://doi.org/10.1186/s40478-022-01415-7
dc.rights.none.fl_str_mv cc by (c) Gelpi, Ellen et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Gelpi, Ellen et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301629

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