RNA editing alterations define manifestation of prion diseases.

Abstract

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.

• Authors: Eirini Kanata, Franc Llorens, Dimitra Dafou, Athanasios Dimitriadis, Katrin Thüne, Konstantinos Xanthopoulos, Nikolaos Bekas, Juan Carlos Espinosa, Matthias Schmitz, Alba Marín-Moreno, Vincenzo Capece, Orr Shormoni, Olivier Andréoletti, Stefan Bonn, Juan María Torres, Isidre Ferrer, Inga Zerr, Theodoros Sklaviadis
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 39 Pg. 19727-19735 (09 24 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31492812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• Prion Proteins
• Prions

Topics

• Animals
• Brain (metabolism)
• Creutzfeldt-Jakob Syndrome (genetics)
• Disease Models, Animal
• Disease Progression
• Gene Expression Profiling (methods)
• Gene Expression Regulation (genetics)
• Genotype
• Humans
• Mice
• Prion Diseases (genetics, metabolism)
• Prion Proteins (genetics)
• Prions (metabolism)
• RNA Editing (genetics, physiology)
• Transcriptome (genetics)