RNA editing alterations define manifestation of prion diseases
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RNA editing alterations define manifestation of prion diseases. / Kanata, Eirini; Llorens, Franc; Dafou, Dimitra; Dimitriadis, Athanasios; Thüne, Katrin; Xanthopoulos, Konstantinos; Bekas, Nikolaos; Espinosa, Juan Carlos; Schmitz, Matthias; Marín-Moreno, Alba; Capece, Vincenzo; Shormoni, Orr; Andréoletti, Olivier; Bonn, Stefan; Torres, Juan María; Ferrer, Isidre; Zerr, Inga; Sklaviadis, Theodoros.
In: P NATL ACAD SCI USA, Vol. 116, No. 39, 24.09.2019, p. 19727-19735.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - RNA editing alterations define manifestation of prion diseases
AU - Kanata, Eirini
AU - Llorens, Franc
AU - Dafou, Dimitra
AU - Dimitriadis, Athanasios
AU - Thüne, Katrin
AU - Xanthopoulos, Konstantinos
AU - Bekas, Nikolaos
AU - Espinosa, Juan Carlos
AU - Schmitz, Matthias
AU - Marín-Moreno, Alba
AU - Capece, Vincenzo
AU - Shormoni, Orr
AU - Andréoletti, Olivier
AU - Bonn, Stefan
AU - Torres, Juan María
AU - Ferrer, Isidre
AU - Zerr, Inga
AU - Sklaviadis, Theodoros
N1 - Copyright © 2019 the Author(s). Published by PNAS.
PY - 2019/9/24
Y1 - 2019/9/24
N2 - Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt-Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
AB - Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt-Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
U2 - 10.1073/pnas.1803521116
DO - 10.1073/pnas.1803521116
M3 - SCORING: Journal article
C2 - 31492812
VL - 116
SP - 19727
EP - 19735
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 39
ER -