Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways

Autores
Feole, Monica; Pozo Devoto, Victorio Martin; Dragišić, Neda; Arnaiz Yépez, Cayetana; Bianchelli, Julieta; Texlová, Kateřina; Kovačovicova, Kristina; Novotny, Jan S.; Havas, Daniel; Falzone, Tomas Luis; Stokin, Gorazd B.
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer’s disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.
Fil: Feole, Monica. International Clinical Research Centre; República Checa. Masaryk University; República Checa. Kings College London (kcl);
Fil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. International Clinical Research Centre; República Checa
Fil: Dragišić, Neda. International Clinical Research Centre; República Checa
Fil: Arnaiz Yépez, Cayetana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Bianchelli, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Texlová, Kateřina. International Clinical Research Centre; República Checa. PsychoGenics; Estados Unidos
Fil: Kovačovicova, Kristina. PsychoGenics; Estados Unidos
Fil: Novotny, Jan S.. International Clinical Research Centre; República Checa. Palacký University Olomouc; República Checa
Fil: Havas, Daniel. PsychoGenics; Estados Unidos
Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Stokin, Gorazd B.. International Clinical Research Centre; República Checa. Palacký University Olomouc; República Checa. University Medical Centre; Eslovenia. Mayo Clinic Cancer Center; Estados Unidos
Materia
Axonal transport
Alzhemier
Kinesin
Dynein
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/258719
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathwaysFeole, MonicaPozo Devoto, Victorio MartinDragišić, NedaArnaiz Yépez, CayetanaBianchelli, JulietaTexlová, KateřinaKovačovicova, KristinaNovotny, Jan S.Havas, DanielFalzone, Tomas LuisStokin, Gorazd B.Axonal transportAlzhemierKinesinDyneinhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer’s disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.Fil: Feole, Monica. International Clinical Research Centre; República Checa. Masaryk University; República Checa. Kings College London (kcl);Fil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. International Clinical Research Centre; República ChecaFil: Dragišić, Neda. International Clinical Research Centre; República ChecaFil: Arnaiz Yépez, Cayetana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Bianchelli, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Texlová, Kateřina. International Clinical Research Centre; República Checa. PsychoGenics; Estados UnidosFil: Kovačovicova, Kristina. PsychoGenics; Estados UnidosFil: Novotny, Jan S.. International Clinical Research Centre; República Checa. Palacký University Olomouc; República ChecaFil: Havas, Daniel. PsychoGenics; Estados UnidosFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Stokin, Gorazd B.. International Clinical Research Centre; República Checa. Palacký University Olomouc; República Checa. University Medical Centre; Eslovenia. Mayo Clinic Cancer Center; Estados UnidosAmerican Society for Biochemistry and Molecular Biology2024-04info: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/11336/258719Feole, Monica; Pozo Devoto, Victorio Martin; Dragišić, Neda; Arnaiz Yépez, Cayetana; Bianchelli, Julieta; et al.; Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 300; 4; 4-2024; 1-180021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0021925824016326info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jbc.2024.107137info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:52:20Zoai:ri.conicet.gov.ar:11336/258719instacron: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 09:52:20.985CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
title Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
spellingShingle Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
Feole, Monica
Axonal transport
Alzhemier
Kinesin
Dynein
title_short Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
title_full Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
title_fullStr Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
title_full_unstemmed Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
title_sort Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways
dc.creator.none.fl_str_mv Feole, Monica
Pozo Devoto, Victorio Martin
Dragišić, Neda
Arnaiz Yépez, Cayetana
Bianchelli, Julieta
Texlová, Kateřina
Kovačovicova, Kristina
Novotny, Jan S.
Havas, Daniel
Falzone, Tomas Luis
Stokin, Gorazd B.
author Feole, Monica
author_facet Feole, Monica
Pozo Devoto, Victorio Martin
Dragišić, Neda
Arnaiz Yépez, Cayetana
Bianchelli, Julieta
Texlová, Kateřina
Kovačovicova, Kristina
Novotny, Jan S.
Havas, Daniel
Falzone, Tomas Luis
Stokin, Gorazd B.
author_role author
author2 Pozo Devoto, Victorio Martin
Dragišić, Neda
Arnaiz Yépez, Cayetana
Bianchelli, Julieta
Texlová, Kateřina
Kovačovicova, Kristina
Novotny, Jan S.
Havas, Daniel
Falzone, Tomas Luis
Stokin, Gorazd B.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Axonal transport
Alzhemier
Kinesin
Dynein
topic Axonal transport
Alzhemier
Kinesin
Dynein
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer’s disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.
Fil: Feole, Monica. International Clinical Research Centre; República Checa. Masaryk University; República Checa. Kings College London (kcl);
Fil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. International Clinical Research Centre; República Checa
Fil: Dragišić, Neda. International Clinical Research Centre; República Checa
Fil: Arnaiz Yépez, Cayetana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Bianchelli, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Texlová, Kateřina. International Clinical Research Centre; República Checa. PsychoGenics; Estados Unidos
Fil: Kovačovicova, Kristina. PsychoGenics; Estados Unidos
Fil: Novotny, Jan S.. International Clinical Research Centre; República Checa. Palacký University Olomouc; República Checa
Fil: Havas, Daniel. PsychoGenics; Estados Unidos
Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Fil: Stokin, Gorazd B.. International Clinical Research Centre; República Checa. Palacký University Olomouc; República Checa. University Medical Centre; Eslovenia. Mayo Clinic Cancer Center; Estados Unidos
description Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer’s disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.
publishDate 2024
dc.date.none.fl_str_mv 2024-04
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/11336/258719
Feole, Monica; Pozo Devoto, Victorio Martin; Dragišić, Neda; Arnaiz Yépez, Cayetana; Bianchelli, Julieta; et al.; Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 300; 4; 4-2024; 1-18
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/258719
identifier_str_mv Feole, Monica; Pozo Devoto, Victorio Martin; Dragišić, Neda; Arnaiz Yépez, Cayetana; Bianchelli, Julieta; et al.; Swedish Alzheimer’s disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 300; 4; 4-2024; 1-18
0021-9258
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://www.sciencedirect.com/science/article/pii/S0021925824016326
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jbc.2024.107137
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
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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