Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration

Aim To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1). Methods In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large-scale transcriptome maps provided by the Allen Human Br...

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Autores: Jiménez Marín, Antonio, Díez Palacio, Ibai, Labayru Isusquiza, Garazi, Sistiaga Berrondo, Andone, Caballero, Maria C., Andres-Benito, Pol, Sepulcre, Jorge, Ferrer, Isidro, López de Munain Arregui, Adolfo José, Cortés Díaz, Jesús María
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/54618
Acceso en línea:http://hdl.handle.net/10810/54618
Access Level:acceso abierto
Palabra clave:Allen Human Brain Atlas
DM1
neuropsychological deficits
structural neuroimaging
synaptic vesicles
volume loss
white-matter abnormalities
cardiac involvement
CGT repeats
brain
expansion
impairment
pattern
dysregulation
cognition
proteins
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oai_identifier_str oai:addi.ehu.eus:10810/54618
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
title Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
spellingShingle Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
Jiménez Marín, Antonio
Allen Human Brain Atlas
DM1
neuropsychological deficits
structural neuroimaging
synaptic vesicles
volume loss
white-matter abnormalities
cardiac involvement
CGT repeats
brain
expansion
impairment
pattern
dysregulation
cognition
proteins
title_short Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
title_full Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
title_fullStr Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
title_full_unstemmed Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
title_sort Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration
dc.creator.none.fl_str_mv Jiménez Marín, Antonio
Díez Palacio, Ibai
Labayru Isusquiza, Garazi
Sistiaga Berrondo, Andone
Caballero, Maria C.
Andres-Benito, Pol
Sepulcre, Jorge
Ferrer, Isidro
López de Munain Arregui, Adolfo José
Cortés Díaz, Jesús María
author Jiménez Marín, Antonio
author_facet Jiménez Marín, Antonio
Díez Palacio, Ibai
Labayru Isusquiza, Garazi
Sistiaga Berrondo, Andone
Caballero, Maria C.
Andres-Benito, Pol
Sepulcre, Jorge
Ferrer, Isidro
López de Munain Arregui, Adolfo José
Cortés Díaz, Jesús María
author_role author
author2 Díez Palacio, Ibai
Labayru Isusquiza, Garazi
Sistiaga Berrondo, Andone
Caballero, Maria C.
Andres-Benito, Pol
Sepulcre, Jorge
Ferrer, Isidro
López de Munain Arregui, Adolfo José
Cortés Díaz, Jesús María
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Allen Human Brain Atlas
DM1
neuropsychological deficits
structural neuroimaging
synaptic vesicles
volume loss
white-matter abnormalities
cardiac involvement
CGT repeats
brain
expansion
impairment
pattern
dysregulation
cognition
proteins
topic Allen Human Brain Atlas
DM1
neuropsychological deficits
structural neuroimaging
synaptic vesicles
volume loss
white-matter abnormalities
cardiac involvement
CGT repeats
brain
expansion
impairment
pattern
dysregulation
cognition
proteins
description Aim To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1). Methods In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large-scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples. Results Twofold: (1) From a list of preselected hypothesis-driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Neuropathological analyses confirmed a highly heterogeneous Tau-pathology in DM1, different to the one in Alzheimer's disease. (2) Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction. Conclusions The combination of large-scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1 that might help define future therapeutic strategies and research into this condition.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/54618
url http://hdl.handle.net/10810/54618
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MINECO/DPI2016-79874-R/
https://onlinelibrary.wiley.com/doi/10.1111/nan.12725
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc/3.0/es/
Atribución-NoComercial 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/3.0/es/
Atribución-NoComercial 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405461220950016
spelling Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegenerationJiménez Marín, AntonioDíez Palacio, IbaiLabayru Isusquiza, GaraziSistiaga Berrondo, AndoneCaballero, Maria C.Andres-Benito, PolSepulcre, JorgeFerrer, IsidroLópez de Munain Arregui, Adolfo JoséCortés Díaz, Jesús MaríaAllen Human Brain AtlasDM1neuropsychological deficitsstructural neuroimagingsynaptic vesiclesvolume losswhite-matter abnormalitiescardiac involvementCGT repeatsbrainexpansionimpairmentpatterndysregulationcognitionproteinsAim To delineate the neurogenetic profiles of brain degeneration patterns in myotonic dystrophy type I (DM1). Methods In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (NDs) were intersected to large-scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples. Results Twofold: (1) From a list of preselected hypothesis-driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Neuropathological analyses confirmed a highly heterogeneous Tau-pathology in DM1, different to the one in Alzheimer's disease. (2) Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction. Conclusions The combination of large-scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1 that might help define future therapeutic strategies and research into this condition.We wish to thank Prof. Virginia Arechavala for providing us with an updated list of relevant genes in DM1, some of which were considered in our study. J.M.C. is funded by Ikerbasque: The Basque Foundation for Science and from the Ministerio de Economia, Industria y Competitividad (Spain) and FEDER (grant DPI2016-79874-R), and from the Department of Economic and Infrastructure Development of the Basque Country (Elkartek Program, KK-2018/00032 and KK-2018/00090). A.L. d. M. was founded by the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional-FEDER (grant PI17/01841), CIBERNED (grant 609), and La Caixa Foundation (grant HR17-00268). A. S. was founded by the Institute of Health Carlos III co-founded by Fondo Europeo de Desarrollo Regional-FEDER (grant PI17/01231), and the Basque Government (grant SAIO08-PE08BF01). A. J.M was partially funded by Euskampus Fundazioa and a predoctoral grant from the Basque Government (PRE_2019_1_ 0070). G.L. was founded by a predoctoral grant from the Basque Government (PRE_2016_1_0187). I.F. was founded from `la Caixa' Foundation under the agreement LCF/PR/HR19/52160007 and was also supported by the Ministry of Economy and Competiveness, Institute of Health Carlos III (co-funded by European Regional Development Fund, ERDF, a way to build Europe): FIS PI17/000809.Wiley202120212021info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/54618reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MINECO/DPI2016-79874-R/https://onlinelibrary.wiley.com/doi/10.1111/nan.12725info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc/3.0/es/This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.Atribución-NoComercial 3.0 Españaoai:addi.ehu.eus:10810/546182026-06-18T09:23:17Z
score 15,301603

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