NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease

Autores
Pullara, Filippo; Forsmann, Madison C.; General, Ignacio; Ayoob, Joseph C.; Furbee, Emily; Castro, Sandra L.; Hu, Xiaoping; Greenamyre, J. Timothy; Di Maio, Roberto
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca2+ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson´s disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca2+/CaM, thus impeding the formation of the CaMKIIα:Ca2+/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca2+/CaM interaction. We observed CaMKIIα:Ca2+/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson´s disease (PD) patients´ specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca2+/CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O2●-) and hydrogen peroxide (H2O2) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca2+/CaM complex disruption associated to a stable Ca2+CAM-independent CaMKIIα kinase activity and intracellular Ca2+ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.
Fil: Pullara, Filippo. University of Pittsburgh; Estados Unidos
Fil: Forsmann, Madison C.. University of Pittsburgh; Estados Unidos
Fil: General, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Ciencias Fisicas. - Universidad Nacional de San Martin. Instituto de Ciencias Fisicas.; Argentina
Fil: Ayoob, Joseph C.. University of Pittsburgh; Estados Unidos
Fil: Furbee, Emily. University of Pittsburgh; Estados Unidos
Fil: Castro, Sandra L.. University of Pittsburgh; Estados Unidos
Fil: Hu, Xiaoping. University of Pittsburgh; Estados Unidos
Fil: Greenamyre, J. Timothy. University of Pittsburgh; Estados Unidos
Fil: Di Maio, Roberto. University of Pittsburgh; Estados Unidos
Materia
CaMKII redox modification
Parkinson disease
disulfide bridge
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/264431
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/264431
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's diseasePullara, FilippoForsmann, Madison C.General, IgnacioAyoob, Joseph C.Furbee, EmilyCastro, Sandra L.Hu, XiaopingGreenamyre, J. TimothyDi Maio, RobertoCaMKII redox modificationParkinson diseasedisulfide bridgehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca2+ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson´s disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca2+/CaM, thus impeding the formation of the CaMKIIα:Ca2+/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca2+/CaM interaction. We observed CaMKIIα:Ca2+/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson´s disease (PD) patients´ specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca2+/CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O2●-) and hydrogen peroxide (H2O2) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca2+/CaM complex disruption associated to a stable Ca2+CAM-independent CaMKIIα kinase activity and intracellular Ca2+ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.Fil: Pullara, Filippo. University of Pittsburgh; Estados UnidosFil: Forsmann, Madison C.. University of Pittsburgh; Estados UnidosFil: General, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Ciencias Fisicas. - Universidad Nacional de San Martin. Instituto de Ciencias Fisicas.; ArgentinaFil: Ayoob, Joseph C.. University of Pittsburgh; Estados UnidosFil: Furbee, Emily. University of Pittsburgh; Estados UnidosFil: Castro, Sandra L.. University of Pittsburgh; Estados UnidosFil: Hu, Xiaoping. University of Pittsburgh; Estados UnidosFil: Greenamyre, J. Timothy. University of Pittsburgh; Estados UnidosFil: Di Maio, Roberto. University of Pittsburgh; Estados UnidosElsevier2024-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/264431Pullara, Filippo; Forsmann, Madison C.; General, Ignacio; Ayoob, Joseph C.; Furbee, Emily; et al.; NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease; Elsevier; Redox Biology; 75; 9-2024; 1-122213-2317CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2213231724002325info:eu-repo/semantics/altIdentifier/doi/10.1016/j.redox.2024.103254info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:58:46Zoai:ri.conicet.gov.ar:11336/264431instacron: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:34982025-09-03 09:58:46.573CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
title NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
spellingShingle NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
Pullara, Filippo
CaMKII redox modification
Parkinson disease
disulfide bridge
title_short NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
title_full NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
title_fullStr NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
title_full_unstemmed NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
title_sort NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease
dc.creator.none.fl_str_mv Pullara, Filippo
Forsmann, Madison C.
General, Ignacio
Ayoob, Joseph C.
Furbee, Emily
Castro, Sandra L.
Hu, Xiaoping
Greenamyre, J. Timothy
Di Maio, Roberto
author Pullara, Filippo
author_facet Pullara, Filippo
Forsmann, Madison C.
General, Ignacio
Ayoob, Joseph C.
Furbee, Emily
Castro, Sandra L.
Hu, Xiaoping
Greenamyre, J. Timothy
Di Maio, Roberto
author_role author
author2 Forsmann, Madison C.
General, Ignacio
Ayoob, Joseph C.
Furbee, Emily
Castro, Sandra L.
Hu, Xiaoping
Greenamyre, J. Timothy
Di Maio, Roberto
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CaMKII redox modification
Parkinson disease
disulfide bridge
topic CaMKII redox modification
Parkinson disease
disulfide bridge
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca2+ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson´s disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca2+/CaM, thus impeding the formation of the CaMKIIα:Ca2+/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca2+/CaM interaction. We observed CaMKIIα:Ca2+/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson´s disease (PD) patients´ specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca2+/CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O2●-) and hydrogen peroxide (H2O2) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca2+/CaM complex disruption associated to a stable Ca2+CAM-independent CaMKIIα kinase activity and intracellular Ca2+ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.
Fil: Pullara, Filippo. University of Pittsburgh; Estados Unidos
Fil: Forsmann, Madison C.. University of Pittsburgh; Estados Unidos
Fil: General, Ignacio. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Ciencias Fisicas. - Universidad Nacional de San Martin. Instituto de Ciencias Fisicas.; Argentina
Fil: Ayoob, Joseph C.. University of Pittsburgh; Estados Unidos
Fil: Furbee, Emily. University of Pittsburgh; Estados Unidos
Fil: Castro, Sandra L.. University of Pittsburgh; Estados Unidos
Fil: Hu, Xiaoping. University of Pittsburgh; Estados Unidos
Fil: Greenamyre, J. Timothy. University of Pittsburgh; Estados Unidos
Fil: Di Maio, Roberto. University of Pittsburgh; Estados Unidos
description Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) signaling in the brain plays a critical role in regulating neuronal Ca2+ homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson´s disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKIIα, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKIIα docking site for Ca2+/CaM, thus impeding the formation of the CaMKIIα:Ca2+/CaM complex, essential for a proper modulation of CaMKIIα kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKIIα:Ca2+/CaM interaction. We observed CaMKIIα:Ca2+/CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson´s disease (PD) patients´ specimens, addressing the high relevance of this event in the disease. CaMKIIα:Ca2+/CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKIIα kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O2●-) and hydrogen peroxide (H2O2) in the brain with implications in PD pathogenesis, is responsible for CaMKIIα:Ca2+/CaM complex disruption associated to a stable Ca2+CAM-independent CaMKIIα kinase activity and intracellular Ca2+ accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKIIα signaling in calcium dysregulation, offering novel insights into PD pathogenesis.
publishDate 2024
dc.date.none.fl_str_mv 2024-09
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/11336/264431
Pullara, Filippo; Forsmann, Madison C.; General, Ignacio; Ayoob, Joseph C.; Furbee, Emily; et al.; NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease; Elsevier; Redox Biology; 75; 9-2024; 1-12
2213-2317
CONICET Digital
CONICET
url http://hdl.handle.net/11336/264431
identifier_str_mv Pullara, Filippo; Forsmann, Madison C.; General, Ignacio; Ayoob, Joseph C.; Furbee, Emily; et al.; NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease; Elsevier; Redox Biology; 75; 9-2024; 1-12
2213-2317
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2213231724002325
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.redox.2024.103254
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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score 12.885934

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