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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/12912

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oai_identifier_str oai:ri.conicet.gov.ar:11336/12912
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv 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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