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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/66499
Ver los metadatos del registro completo
id |
CONICETDig_603c45fdddfa93f40d18f2ea91070c17 |
---|---|
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 |
_version_ |
1844613893515640832 |
score |
13.070432 |