Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation

Autores
Leo, Lanfranco; Weissmann, Carina; Burns, Matthew; Kang, Minsu; Song, Yuyu; Qiang, Liang; Brady, Scott T.; Baas, Peter W.; Morfini, Gerardo
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis. However, the mechanisms linking SPAST mutations to such deficits remain largely unknown. Experiments presented here using isolated squid axoplasm reveal inhibition of FAT as a common toxic effect elicited by spastin proteins with different HSP mutations, independent of microtubule-binding or severing activity. Mutant spastin proteins produce this toxic effect only when presented as the tissue-specific M1 isoform, not when presented as the ubiquitously-expressed shorter M87 isoform. Biochemical and pharmacological experiments further indicate that the toxic effects of mutant M1 spastins on FAT involve casein kinase 2 (CK2) activation. In mammalian cells, expression of mutant M1 spastins, but not their mutant M87 counterparts, promotes abnormalities in the distribution of intracellular organelles that are correctable by pharmacological CK2 inhibition. Collectively, these results demonstrate isoform-specific toxic effects of mutant M1 spastin on FAT, and identify CK2 as a critical mediator of these effects.
Fil: Leo, Lanfranco. Drexel University College of Medicine; Estados Unidos
Fil: Weissmann, Carina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Chicago; Estados Unidos
Fil: Burns, Matthew. University of Chicago; Estados Unidos
Fil: Kang, Minsu. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
Fil: Song, Yuyu. Marine Biological Laboratory; Estados Unidos. Yale University; Estados Unidos
Fil: Qiang, Liang. Drexel University College of Medicine; Estados Unidos
Fil: Brady, Scott T.. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
Fil: Baas, Peter W.. Drexel University College of Medicine; Estados Unidos
Fil: Morfini, Gerardo. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
Materia
ESPASTINA
TRANSPORTE AXONAL
MOTORES MOLECULARES
CK2
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:11336/66499

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oai_identifier_str oai:ri.conicet.gov.ar:11336/66499
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activationLeo, LanfrancoWeissmann, CarinaBurns, MatthewKang, MinsuSong, YuyuQiang, LiangBrady, Scott T.Baas, Peter W.Morfini, GerardoESPASTINATRANSPORTE AXONALMOTORES MOLECULARESCK2https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis. However, the mechanisms linking SPAST mutations to such deficits remain largely unknown. Experiments presented here using isolated squid axoplasm reveal inhibition of FAT as a common toxic effect elicited by spastin proteins with different HSP mutations, independent of microtubule-binding or severing activity. Mutant spastin proteins produce this toxic effect only when presented as the tissue-specific M1 isoform, not when presented as the ubiquitously-expressed shorter M87 isoform. Biochemical and pharmacological experiments further indicate that the toxic effects of mutant M1 spastins on FAT involve casein kinase 2 (CK2) activation. In mammalian cells, expression of mutant M1 spastins, but not their mutant M87 counterparts, promotes abnormalities in the distribution of intracellular organelles that are correctable by pharmacological CK2 inhibition. Collectively, these results demonstrate isoform-specific toxic effects of mutant M1 spastin on FAT, and identify CK2 as a critical mediator of these effects.Fil: Leo, Lanfranco. Drexel University College of Medicine; Estados UnidosFil: Weissmann, Carina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Chicago; Estados UnidosFil: Burns, Matthew. University of Chicago; Estados UnidosFil: Kang, Minsu. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados UnidosFil: Song, Yuyu. Marine Biological Laboratory; Estados Unidos. Yale University; Estados UnidosFil: Qiang, Liang. Drexel University College of Medicine; Estados UnidosFil: Brady, Scott T.. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados UnidosFil: Baas, Peter W.. Drexel University College of Medicine; Estados UnidosFil: Morfini, Gerardo. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados UnidosOxford University Press2017-06info: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/11336/66499Leo, Lanfranco; Weissmann, Carina; Burns, Matthew; Kang, Minsu; Song, Yuyu; et al.; Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation; Oxford University Press; Human molecular genetics; 26; 12; 6-2017; 2321-23341460-20830964-6906CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1093/hmg/ddx125info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/hmg/article/26/12/2321/3111723info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:05:34Zoai:ri.conicet.gov.ar:11336/66499instacron: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 10:05:35.163CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
title Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
spellingShingle Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
Leo, Lanfranco
ESPASTINA
TRANSPORTE AXONAL
MOTORES MOLECULARES
CK2
title_short Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
title_full Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
title_fullStr Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
title_full_unstemmed Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
title_sort Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
dc.creator.none.fl_str_mv Leo, Lanfranco
Weissmann, Carina
Burns, Matthew
Kang, Minsu
Song, Yuyu
Qiang, Liang
Brady, Scott T.
Baas, Peter W.
Morfini, Gerardo
author Leo, Lanfranco
author_facet Leo, Lanfranco
Weissmann, Carina
Burns, Matthew
Kang, Minsu
Song, Yuyu
Qiang, Liang
Brady, Scott T.
Baas, Peter W.
Morfini, Gerardo
author_role author
author2 Weissmann, Carina
Burns, Matthew
Kang, Minsu
Song, Yuyu
Qiang, Liang
Brady, Scott T.
Baas, Peter W.
Morfini, Gerardo
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ESPASTINA
TRANSPORTE AXONAL
MOTORES MOLECULARES
CK2
topic ESPASTINA
TRANSPORTE AXONAL
MOTORES MOLECULARES
CK2
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis. However, the mechanisms linking SPAST mutations to such deficits remain largely unknown. Experiments presented here using isolated squid axoplasm reveal inhibition of FAT as a common toxic effect elicited by spastin proteins with different HSP mutations, independent of microtubule-binding or severing activity. Mutant spastin proteins produce this toxic effect only when presented as the tissue-specific M1 isoform, not when presented as the ubiquitously-expressed shorter M87 isoform. Biochemical and pharmacological experiments further indicate that the toxic effects of mutant M1 spastins on FAT involve casein kinase 2 (CK2) activation. In mammalian cells, expression of mutant M1 spastins, but not their mutant M87 counterparts, promotes abnormalities in the distribution of intracellular organelles that are correctable by pharmacological CK2 inhibition. Collectively, these results demonstrate isoform-specific toxic effects of mutant M1 spastin on FAT, and identify CK2 as a critical mediator of these effects.
Fil: Leo, Lanfranco. Drexel University College of Medicine; Estados Unidos
Fil: Weissmann, Carina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Chicago; Estados Unidos
Fil: Burns, Matthew. University of Chicago; Estados Unidos
Fil: Kang, Minsu. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
Fil: Song, Yuyu. Marine Biological Laboratory; Estados Unidos. Yale University; Estados Unidos
Fil: Qiang, Liang. Drexel University College of Medicine; Estados Unidos
Fil: Brady, Scott T.. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
Fil: Baas, Peter W.. Drexel University College of Medicine; Estados Unidos
Fil: Morfini, Gerardo. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
description Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis. However, the mechanisms linking SPAST mutations to such deficits remain largely unknown. Experiments presented here using isolated squid axoplasm reveal inhibition of FAT as a common toxic effect elicited by spastin proteins with different HSP mutations, independent of microtubule-binding or severing activity. Mutant spastin proteins produce this toxic effect only when presented as the tissue-specific M1 isoform, not when presented as the ubiquitously-expressed shorter M87 isoform. Biochemical and pharmacological experiments further indicate that the toxic effects of mutant M1 spastins on FAT involve casein kinase 2 (CK2) activation. In mammalian cells, expression of mutant M1 spastins, but not their mutant M87 counterparts, promotes abnormalities in the distribution of intracellular organelles that are correctable by pharmacological CK2 inhibition. Collectively, these results demonstrate isoform-specific toxic effects of mutant M1 spastin on FAT, and identify CK2 as a critical mediator of these effects.
publishDate 2017
dc.date.none.fl_str_mv 2017-06
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/11336/66499
Leo, Lanfranco; Weissmann, Carina; Burns, Matthew; Kang, Minsu; Song, Yuyu; et al.; Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation; Oxford University Press; Human molecular genetics; 26; 12; 6-2017; 2321-2334
1460-2083
0964-6906
CONICET Digital
CONICET
url http://hdl.handle.net/11336/66499
identifier_str_mv Leo, Lanfranco; Weissmann, Carina; Burns, Matthew; Kang, Minsu; Song, Yuyu; et al.; Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation; Oxford University Press; Human molecular genetics; 26; 12; 6-2017; 2321-2334
1460-2083
0964-6906
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/hmg/ddx125
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/hmg/article/26/12/2321/3111723
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 Oxford University Press
publisher.none.fl_str_mv Oxford University Press
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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