Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction
- Autores
- Li, A.; Zhou, C.; Moore, J.; Zhang, P.; Tsai, T. H.; Lee, H. C.; Romano, D. M.; McKee, M. L.; Schoenfeld, D. A.; Serra, M. J.; Raygor, K.; Cantiello, Horacio Fabio; Fujimoto, J. G.; Tanzi, R. E.
- Año de publicación
- 2011
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Mutations in the presenilin genes cause the majority of early-onset familial Alzheimers disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.
Fil: Li, A.. Harvard Medical School; Estados Unidos
Fil: Zhou, C.. Massachusetts Institute of Technology; Estados Unidos
Fil: Moore, J.. Harvard Medical School; Estados Unidos
Fil: Zhang, P.. Harvard Medical School; Estados Unidos
Fil: Tsai, T. H.. Massachusetts Institute of Technology; Estados Unidos
Fil: Lee, H. C.. Massachusetts Institute of Technology; Estados Unidos
Fil: Romano, D. M.. Harvard Medical School; Estados Unidos
Fil: McKee, M. L.. Harvard Medical School; Estados Unidos
Fil: Schoenfeld, D. A.. Harvard University. Harvard School Of Public Health; Estados Unidos
Fil: Serra, M. J.. Harvard Medical School; Estados Unidos
Fil: Raygor, K.. Harvard Medical School; Estados Unidos
Fil: Cantiello, Horacio Fabio. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Fujimoto, J. G.. Massachusetts Institute of Technology; Estados Unidos
Fil: Tanzi, R. E.. Harvard Medical School; Estados Unidos - Materia
-
Alzheimer's Disease-Associated Presenilin Gene
cardiac disfunction - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/12912
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Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac DysfunctionLi, A.Zhou, C.Moore, J.Zhang, P.Tsai, T. H.Lee, H. C.Romano, D. M.McKee, M. L.Schoenfeld, D. A.Serra, M. J.Raygor, K.Cantiello, Horacio FabioFujimoto, J. G.Tanzi, R. E.Alzheimer's Disease-Associated Presenilin Genecardiac disfunctionhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Mutations in the presenilin genes cause the majority of early-onset familial Alzheimers disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.Fil: Li, A.. Harvard Medical School; Estados UnidosFil: Zhou, C.. Massachusetts Institute of Technology; Estados UnidosFil: Moore, J.. Harvard Medical School; Estados UnidosFil: Zhang, P.. Harvard Medical School; Estados UnidosFil: Tsai, T. H.. Massachusetts Institute of Technology; Estados UnidosFil: Lee, H. C.. Massachusetts Institute of Technology; Estados UnidosFil: Romano, D. M.. Harvard Medical School; Estados UnidosFil: McKee, M. L.. Harvard Medical School; Estados UnidosFil: Schoenfeld, D. A.. Harvard University. Harvard School Of Public Health; Estados UnidosFil: Serra, M. J.. Harvard Medical School; Estados UnidosFil: Raygor, K.. Harvard Medical School; Estados UnidosFil: Cantiello, Horacio Fabio. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Fujimoto, J. G.. Massachusetts Institute of Technology; Estados UnidosFil: Tanzi, R. E.. Harvard Medical School; Estados UnidosBentham Science Publishers2011-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/12912Li, A.; Zhou, C.; Moore, J.; Zhang, P.; Tsai, T. H.; et al.; Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction; Bentham Science Publishers; Current Alzheimer Research; 8; 3; 4-2011; 313-3221567-2050enginfo:eu-repo/semantics/altIdentifier/url/http://www.eurekaselect.com/87978/articleinfo:eu-repo/semantics/altIdentifier/doi/10.2174/156720511795563746info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179576/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:17:15Zoai:ri.conicet.gov.ar:11336/12912instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:17:15.9CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction |
title |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction |
spellingShingle |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction Li, A. Alzheimer's Disease-Associated Presenilin Gene cardiac disfunction |
title_short |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction |
title_full |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction |
title_fullStr |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction |
title_full_unstemmed |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction |
title_sort |
Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction |
dc.creator.none.fl_str_mv |
Li, A. Zhou, C. Moore, J. Zhang, P. Tsai, T. H. Lee, H. C. Romano, D. M. McKee, M. L. Schoenfeld, D. A. Serra, M. J. Raygor, K. Cantiello, Horacio Fabio Fujimoto, J. G. Tanzi, R. E. |
author |
Li, A. |
author_facet |
Li, A. Zhou, C. Moore, J. Zhang, P. Tsai, T. H. Lee, H. C. Romano, D. M. McKee, M. L. Schoenfeld, D. A. Serra, M. J. Raygor, K. Cantiello, Horacio Fabio Fujimoto, J. G. Tanzi, R. E. |
author_role |
author |
author2 |
Zhou, C. Moore, J. Zhang, P. Tsai, T. H. Lee, H. C. Romano, D. M. McKee, M. L. Schoenfeld, D. A. Serra, M. J. Raygor, K. Cantiello, Horacio Fabio Fujimoto, J. G. Tanzi, R. E. |
author2_role |
author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
Alzheimer's Disease-Associated Presenilin Gene cardiac disfunction |
topic |
Alzheimer's Disease-Associated Presenilin Gene cardiac disfunction |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Mutations in the presenilin genes cause the majority of early-onset familial Alzheimers disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis. Fil: Li, A.. Harvard Medical School; Estados Unidos Fil: Zhou, C.. Massachusetts Institute of Technology; Estados Unidos Fil: Moore, J.. Harvard Medical School; Estados Unidos Fil: Zhang, P.. Harvard Medical School; Estados Unidos Fil: Tsai, T. H.. Massachusetts Institute of Technology; Estados Unidos Fil: Lee, H. C.. Massachusetts Institute of Technology; Estados Unidos Fil: Romano, D. M.. Harvard Medical School; Estados Unidos Fil: McKee, M. L.. Harvard Medical School; Estados Unidos Fil: Schoenfeld, D. A.. Harvard University. Harvard School Of Public Health; Estados Unidos Fil: Serra, M. J.. Harvard Medical School; Estados Unidos Fil: Raygor, K.. Harvard Medical School; Estados Unidos Fil: Cantiello, Horacio Fabio. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Fujimoto, J. G.. Massachusetts Institute of Technology; Estados Unidos Fil: Tanzi, R. E.. Harvard Medical School; Estados Unidos |
description |
Mutations in the presenilin genes cause the majority of early-onset familial Alzheimers disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis. |
publishDate |
2011 |
dc.date.none.fl_str_mv |
2011-04 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/12912 Li, A.; Zhou, C.; Moore, J.; Zhang, P.; Tsai, T. H.; et al.; Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction; Bentham Science Publishers; Current Alzheimer Research; 8; 3; 4-2011; 313-322 1567-2050 |
url |
http://hdl.handle.net/11336/12912 |
identifier_str_mv |
Li, A.; Zhou, C.; Moore, J.; Zhang, P.; Tsai, T. H.; et al.; Changes in the Expression of the Alzheimer's Disease-Associated Presenilin Gene in Drosophila Heart Leads to Cardiac Dysfunction; Bentham Science Publishers; Current Alzheimer Research; 8; 3; 4-2011; 313-322 1567-2050 |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://www.eurekaselect.com/87978/article info:eu-repo/semantics/altIdentifier/doi/10.2174/156720511795563746 info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179576/ |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Bentham Science Publishers |
publisher.none.fl_str_mv |
Bentham Science Publishers |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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13.070432 |