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Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is characterized by a broad phenotypic spectrum regarding symptoms, progression, and molecular features. Current sporadic CJD (sCJD) classification recognizes six main clinical-pathological phenotypes. This work investigates the molecular basis of the phenotypic heter...

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Autores principales: Tarozzi, Martina, Baiardi, Simone, Sala, Claudia, Bartoletti-Stella, Anna, Parchi, Piero, Capellari, Sabina, Castellani, Gastone
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749175/
https://www.ncbi.nlm.nih.gov/pubmed/36517866
http://dx.doi.org/10.1186/s40478-022-01483-9
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author Tarozzi, Martina
Baiardi, Simone
Sala, Claudia
Bartoletti-Stella, Anna
Parchi, Piero
Capellari, Sabina
Castellani, Gastone
author_facet Tarozzi, Martina
Baiardi, Simone
Sala, Claudia
Bartoletti-Stella, Anna
Parchi, Piero
Capellari, Sabina
Castellani, Gastone
author_sort Tarozzi, Martina
collection PubMed
description Creutzfeldt-Jakob disease (CJD) is characterized by a broad phenotypic spectrum regarding symptoms, progression, and molecular features. Current sporadic CJD (sCJD) classification recognizes six main clinical-pathological phenotypes. This work investigates the molecular basis of the phenotypic heterogeneity of prion diseases through a multi-omics analysis of the two most common sCJD subtypes: MM1 and VV2. We performed DNA target sequencing on 118 genes on a cohort of 48 CJD patients and full exome RNA sequencing on post-mortem frontal cortex tissue on a subset of this cohort. DNA target sequencing identified multiple potential genetic contributors to the disease onset and phenotype, both in terms of coding, damaging-predicted variants, and enriched groups of SNPs in the whole cohort and the two subtypes. The results highlight a different functional impairment, with VV2 associated with higher impairment of the pathways related to dopamine secretion, regulation of calcium release and GABA signaling, showing some similarities with Parkinson’s disease both on a genomic and a transcriptomic level. MM1 showed a gene expression profile with several traits shared with different neurodegenerative, without an apparent distinctive characteristic or similarities with a specific disease. In addition, integrating genomic and transcriptomic data led to the discovery of several sites of ADAR-mediated RNA editing events, confirming and expanding previous findings in animal models. On the transcriptomic level, this work represents the first application of RNA sequencing on CJD human brain samples. Here, a good clusterization of the transcriptomic profiles of the two subtypes was achieved, together with the finding of several differently impaired pathways between the two subtypes. The results add to the understanding of the molecular features associated with sporadic CJD and its most common subtypes, revealing strain-specific genetic signatures and functional similarities between VV2 and Parkinson’s disease and providing preliminary evidence of RNA editing modifications in human sCJD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01483-9.
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spelling pubmed-97491752022-12-15 Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease Tarozzi, Martina Baiardi, Simone Sala, Claudia Bartoletti-Stella, Anna Parchi, Piero Capellari, Sabina Castellani, Gastone Acta Neuropathol Commun Research Creutzfeldt-Jakob disease (CJD) is characterized by a broad phenotypic spectrum regarding symptoms, progression, and molecular features. Current sporadic CJD (sCJD) classification recognizes six main clinical-pathological phenotypes. This work investigates the molecular basis of the phenotypic heterogeneity of prion diseases through a multi-omics analysis of the two most common sCJD subtypes: MM1 and VV2. We performed DNA target sequencing on 118 genes on a cohort of 48 CJD patients and full exome RNA sequencing on post-mortem frontal cortex tissue on a subset of this cohort. DNA target sequencing identified multiple potential genetic contributors to the disease onset and phenotype, both in terms of coding, damaging-predicted variants, and enriched groups of SNPs in the whole cohort and the two subtypes. The results highlight a different functional impairment, with VV2 associated with higher impairment of the pathways related to dopamine secretion, regulation of calcium release and GABA signaling, showing some similarities with Parkinson’s disease both on a genomic and a transcriptomic level. MM1 showed a gene expression profile with several traits shared with different neurodegenerative, without an apparent distinctive characteristic or similarities with a specific disease. In addition, integrating genomic and transcriptomic data led to the discovery of several sites of ADAR-mediated RNA editing events, confirming and expanding previous findings in animal models. On the transcriptomic level, this work represents the first application of RNA sequencing on CJD human brain samples. Here, a good clusterization of the transcriptomic profiles of the two subtypes was achieved, together with the finding of several differently impaired pathways between the two subtypes. The results add to the understanding of the molecular features associated with sporadic CJD and its most common subtypes, revealing strain-specific genetic signatures and functional similarities between VV2 and Parkinson’s disease and providing preliminary evidence of RNA editing modifications in human sCJD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-022-01483-9. BioMed Central 2022-12-14 /pmc/articles/PMC9749175/ /pubmed/36517866 http://dx.doi.org/10.1186/s40478-022-01483-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Tarozzi, Martina
Baiardi, Simone
Sala, Claudia
Bartoletti-Stella, Anna
Parchi, Piero
Capellari, Sabina
Castellani, Gastone
Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease
title Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease
title_full Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease
title_fullStr Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease
title_full_unstemmed Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease
title_short Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease
title_sort genomic, transcriptomic and rna editing analysis of human mm1 and vv2 sporadic creutzfeldt-jakob disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749175/
https://www.ncbi.nlm.nih.gov/pubmed/36517866
http://dx.doi.org/10.1186/s40478-022-01483-9
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