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...
| Authors: | ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2021 |
| Country: | España |
| Institution: | Universidad del País Vasco |
| Repository: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/54618 |
| Online Access: | http://hdl.handle.net/10810/54618 |
| Access Level: | Open access |
| Keyword: | 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 |
| _version_ | 1878731418372145152 |
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| author | Jiménez Marín, Antonio |
| 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 |
| author_browse | Andres-Benito, Pol Caballero, Maria C. Cortés Díaz, Jesús María Díez Palacio, Ibai Ferrer, Isidro Jiménez Marín, Antonio Labayru Isusquiza, Garazi López de Munain Arregui, Adolfo José Sepulcre, Jorge Sistiaga Berrondo, Andone |
| 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 |
| collection | Addi. Archivo Digital para la Docencia y la Investigación |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_2f3000fd01fefc5b34dbbc23a4e271b8 |
| institution | Universidad del País Vasco |
| instname_str | Universidad del País Vasco |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:addi.ehu.eus:10810/54618 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| publisher | Wiley |
| publisherStr | Wiley |
| reponame_str | Addi. Archivo Digital para la Docencia y la Investigación |
| spelling | Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration 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 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 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. 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. Wiley http://hdl.handle.net/10810/54618 |
| 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 | 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_short | 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 |
| 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 |
| topic_facet | 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 |
| url | http://hdl.handle.net/10810/54618 |