Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon

Autores
Zorgniotti, Agustina; Ditamo, Yanina; Arce, Carlos Angel; Bisig, Carlos Gaston
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
L-dopa is the most effective drug used to date for management of Parkinson's disease symptoms. Unfortunately, long-term administration of L-dopa often results in development of motor disorders, including dyskinesias. Despite extensive research on L-dopa-induced dyskinesia, its pathogenesis remains poorly understood. We demonstrated previously that L-dopa can be post-translationally incorporated into the C-terminus of α-tubulin in living cells. In the present study, we investigated the effect of the presence of L-dopa-tubulin-enriched microtubules on mitochondrial traffic mediated by molecular motor KIF5B. Using biochemical approaches in combination with experiments on neuronal cell lines and mouse hippocampal primary cultures, we demonstrated that L-dopa incorporation into tubulin is irreversible. Transport of mitochondria along the axon was altered after L-dopa treatment of cells. In L-dopa-treated cells, mitochondria had reduced ability to reach the distal segment of the axon, spent more time in pause, and showed reduced velocity of anterograde movement. KIF5B motor, a member of the kinesin family involved in mitochondrial transport in neurons, showed reduced affinity for Dopa-tubulin-containing microtubules. Our findings, taken together, suggest that tyrosination state of tubulin (and microtubules) is altered by L-dopa incorporation into tubulin; the gradual increase in amount of altered microtubules affects microtubule functioning, impairs mitochondrial traffic and distribution, and this could be relevant in Parkinson's disease patients chronically treated with L-dopa.
Fil: Zorgniotti, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Ditamo, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Arce, Carlos Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Bisig, Carlos Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Materia
DOPA-TUBULIN
L-DOPA INCORPORATION
L-DOPA TREATMENT, MICROTUBULES, MITOCHONDRIA TRAFFIC
PARKINSON'S DISEASE
TYR-TUBULIN
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/143965
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/143965
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axonZorgniotti, AgustinaDitamo, YaninaArce, Carlos AngelBisig, Carlos GastonDOPA-TUBULINL-DOPA INCORPORATIONL-DOPA TREATMENT, MICROTUBULES, MITOCHONDRIA TRAFFICPARKINSON'S DISEASETYR-TUBULINhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3L-dopa is the most effective drug used to date for management of Parkinson's disease symptoms. Unfortunately, long-term administration of L-dopa often results in development of motor disorders, including dyskinesias. Despite extensive research on L-dopa-induced dyskinesia, its pathogenesis remains poorly understood. We demonstrated previously that L-dopa can be post-translationally incorporated into the C-terminus of α-tubulin in living cells. In the present study, we investigated the effect of the presence of L-dopa-tubulin-enriched microtubules on mitochondrial traffic mediated by molecular motor KIF5B. Using biochemical approaches in combination with experiments on neuronal cell lines and mouse hippocampal primary cultures, we demonstrated that L-dopa incorporation into tubulin is irreversible. Transport of mitochondria along the axon was altered after L-dopa treatment of cells. In L-dopa-treated cells, mitochondria had reduced ability to reach the distal segment of the axon, spent more time in pause, and showed reduced velocity of anterograde movement. KIF5B motor, a member of the kinesin family involved in mitochondrial transport in neurons, showed reduced affinity for Dopa-tubulin-containing microtubules. Our findings, taken together, suggest that tyrosination state of tubulin (and microtubules) is altered by L-dopa incorporation into tubulin; the gradual increase in amount of altered microtubules affects microtubule functioning, impairs mitochondrial traffic and distribution, and this could be relevant in Parkinson's disease patients chronically treated with L-dopa.Fil: Zorgniotti, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Ditamo, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Arce, Carlos Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Bisig, Carlos Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaAcademic Press Inc Elsevier Science2021-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/143965Zorgniotti, Agustina; Ditamo, Yanina; Arce, Carlos Angel; Bisig, Carlos Gaston; Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon; Academic Press Inc Elsevier Science; Neurobiology of Disease; 147; 1-2021; 105-1640969-9961CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2020.105164info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996120304393info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:42:40Zoai:ri.conicet.gov.ar:11336/143965instacron: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:34982025-10-22 11:42:40.532CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
title Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
spellingShingle Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
Zorgniotti, Agustina
DOPA-TUBULIN
L-DOPA INCORPORATION
L-DOPA TREATMENT, MICROTUBULES, MITOCHONDRIA TRAFFIC
PARKINSON'S DISEASE
TYR-TUBULIN
title_short Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
title_full Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
title_fullStr Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
title_full_unstemmed Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
title_sort Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon
dc.creator.none.fl_str_mv Zorgniotti, Agustina
Ditamo, Yanina
Arce, Carlos Angel
Bisig, Carlos Gaston
author Zorgniotti, Agustina
author_facet Zorgniotti, Agustina
Ditamo, Yanina
Arce, Carlos Angel
Bisig, Carlos Gaston
author_role author
author2 Ditamo, Yanina
Arce, Carlos Angel
Bisig, Carlos Gaston
author2_role author
author
author
dc.subject.none.fl_str_mv DOPA-TUBULIN
L-DOPA INCORPORATION
L-DOPA TREATMENT, MICROTUBULES, MITOCHONDRIA TRAFFIC
PARKINSON'S DISEASE
TYR-TUBULIN
topic DOPA-TUBULIN
L-DOPA INCORPORATION
L-DOPA TREATMENT, MICROTUBULES, MITOCHONDRIA TRAFFIC
PARKINSON'S DISEASE
TYR-TUBULIN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv L-dopa is the most effective drug used to date for management of Parkinson's disease symptoms. Unfortunately, long-term administration of L-dopa often results in development of motor disorders, including dyskinesias. Despite extensive research on L-dopa-induced dyskinesia, its pathogenesis remains poorly understood. We demonstrated previously that L-dopa can be post-translationally incorporated into the C-terminus of α-tubulin in living cells. In the present study, we investigated the effect of the presence of L-dopa-tubulin-enriched microtubules on mitochondrial traffic mediated by molecular motor KIF5B. Using biochemical approaches in combination with experiments on neuronal cell lines and mouse hippocampal primary cultures, we demonstrated that L-dopa incorporation into tubulin is irreversible. Transport of mitochondria along the axon was altered after L-dopa treatment of cells. In L-dopa-treated cells, mitochondria had reduced ability to reach the distal segment of the axon, spent more time in pause, and showed reduced velocity of anterograde movement. KIF5B motor, a member of the kinesin family involved in mitochondrial transport in neurons, showed reduced affinity for Dopa-tubulin-containing microtubules. Our findings, taken together, suggest that tyrosination state of tubulin (and microtubules) is altered by L-dopa incorporation into tubulin; the gradual increase in amount of altered microtubules affects microtubule functioning, impairs mitochondrial traffic and distribution, and this could be relevant in Parkinson's disease patients chronically treated with L-dopa.
Fil: Zorgniotti, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Ditamo, Yanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Arce, Carlos Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
Fil: Bisig, Carlos Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina
description L-dopa is the most effective drug used to date for management of Parkinson's disease symptoms. Unfortunately, long-term administration of L-dopa often results in development of motor disorders, including dyskinesias. Despite extensive research on L-dopa-induced dyskinesia, its pathogenesis remains poorly understood. We demonstrated previously that L-dopa can be post-translationally incorporated into the C-terminus of α-tubulin in living cells. In the present study, we investigated the effect of the presence of L-dopa-tubulin-enriched microtubules on mitochondrial traffic mediated by molecular motor KIF5B. Using biochemical approaches in combination with experiments on neuronal cell lines and mouse hippocampal primary cultures, we demonstrated that L-dopa incorporation into tubulin is irreversible. Transport of mitochondria along the axon was altered after L-dopa treatment of cells. In L-dopa-treated cells, mitochondria had reduced ability to reach the distal segment of the axon, spent more time in pause, and showed reduced velocity of anterograde movement. KIF5B motor, a member of the kinesin family involved in mitochondrial transport in neurons, showed reduced affinity for Dopa-tubulin-containing microtubules. Our findings, taken together, suggest that tyrosination state of tubulin (and microtubules) is altered by L-dopa incorporation into tubulin; the gradual increase in amount of altered microtubules affects microtubule functioning, impairs mitochondrial traffic and distribution, and this could be relevant in Parkinson's disease patients chronically treated with L-dopa.
publishDate 2021
dc.date.none.fl_str_mv 2021-01
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/11336/143965
Zorgniotti, Agustina; Ditamo, Yanina; Arce, Carlos Angel; Bisig, Carlos Gaston; Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon; Academic Press Inc Elsevier Science; Neurobiology of Disease; 147; 1-2021; 105-164
0969-9961
CONICET Digital
CONICET
url http://hdl.handle.net/11336/143965
identifier_str_mv Zorgniotti, Agustina; Ditamo, Yanina; Arce, Carlos Angel; Bisig, Carlos Gaston; Irreversible incorporation of L-dopa into the C-terminus of α-tubulin inhibits binding of molecular motor KIF5B to microtubules and alters mitochondrial traffic along the axon; Academic Press Inc Elsevier Science; Neurobiology of Disease; 147; 1-2021; 105-164
0969-9961
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2020.105164
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996120304393
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
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 12.982451

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