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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/258719
Ver los metadatos del registro completo
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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 Técnicas2025-09-03T09:53:19Zoai: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:34982025-09-03 09:53:20.113CONICET 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 |
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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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13.13397 |