Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis
Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of...
| Autores: | , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2013 |
| País: | España |
| Institución: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/23584 |
| Acceso en línea: | http://hdl.handle.net/10230/23584 http://dx.doi.org/10.1371/journal.pone.0074203 |
| Access Level: | acceso abierto |
| Palabra clave: | Calci -- Metabolisme Alzheimer, Malaltia d&apos Homeòstasi |
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Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasisRubio Moscardó, FannyBosch Morató, Mònica, 1986-Plata, CristinaGené, GemmaMuñoz López, Francisco José, 1964-Valverde, M. A. (Miguel Ángel), 1963-Clarimón Echevarría, JordiCalci -- MetabolismeAlzheimer, Malaltia d&aposHomeòstasiCalcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.This study was supported by grants from Instituto de Salud Carlos III (PI12/01311, PI10/000587, Red HERACLES RD12/0042/0014), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain), Spanish Ministry of Economy and Competiveness (SAF2012-38140), FEDER Funds, and Generalitat de Catalunya (SGR05-266). Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, the Strategic Funding of the University on Eastern Finland (UEF-Brain) (to M.H and H.S). M.A.V. is the recipient of an ICREA Academia AwardPublic Library of Science (PLoS)201520152013info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/23584http://dx.doi.org/10.1371/journal.pone.0074203reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésPLoS ONE. 2013;8(9):e74203info:eu-repo/grantAgreement/ES/3PN/SAF2012-38140© 2013 Rubio-Moscardo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedinfo:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/235842026-06-12T07:21:37Z |
| dc.title.none.fl_str_mv |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis |
| title |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis |
| spellingShingle |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis Rubio Moscardó, Fanny Calci -- Metabolisme Alzheimer, Malaltia d&apos Homeòstasi |
| title_short |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis |
| title_full |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis |
| title_fullStr |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis |
| title_full_unstemmed |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis |
| title_sort |
Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset alzheimer's disease patients alter calcium homeostasis |
| dc.creator.none.fl_str_mv |
Rubio Moscardó, Fanny Bosch Morató, Mònica, 1986- Plata, Cristina Gené, Gemma Muñoz López, Francisco José, 1964- Valverde, M. A. (Miguel Ángel), 1963- Clarimón Echevarría, Jordi |
| author |
Rubio Moscardó, Fanny |
| author_facet |
Rubio Moscardó, Fanny Bosch Morató, Mònica, 1986- Plata, Cristina Gené, Gemma Muñoz López, Francisco José, 1964- Valverde, M. A. (Miguel Ángel), 1963- Clarimón Echevarría, Jordi |
| author_role |
author |
| author2 |
Bosch Morató, Mònica, 1986- Plata, Cristina Gené, Gemma Muñoz López, Francisco José, 1964- Valverde, M. A. (Miguel Ángel), 1963- Clarimón Echevarría, Jordi |
| author2_role |
author author author author author author |
| dc.subject.none.fl_str_mv |
Calci -- Metabolisme Alzheimer, Malaltia d&apos Homeòstasi |
| topic |
Calci -- Metabolisme Alzheimer, Malaltia d&apos Homeòstasi |
| description |
Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimer’s disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca2+-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca2+ permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca2+ influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca2+ influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca2+ dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade. |
| publishDate |
2013 |
| dc.date.none.fl_str_mv |
2013 2015 2015 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/23584 http://dx.doi.org/10.1371/journal.pone.0074203 |
| url |
http://hdl.handle.net/10230/23584 http://dx.doi.org/10.1371/journal.pone.0074203 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
PLoS ONE. 2013;8(9):e74203 info:eu-repo/grantAgreement/ES/3PN/SAF2012-38140 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Public Library of Science (PLoS) |
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Public Library of Science (PLoS) |
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reponame:Repositorio Digital de la UPF instname:Universitat Pompeu Fabra |
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Universitat Pompeu Fabra |
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Repositorio Digital de la UPF |
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Repositorio Digital de la UPF |
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