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dc.contributor.author
Leo, Lanfranco
dc.contributor.author
Weissmann, Carina
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dc.contributor.author
Burns, Matthew
dc.contributor.author
Kang, Minsu
dc.contributor.author
Song, Yuyu
dc.contributor.author
Qiang, Liang
dc.contributor.author
Brady, Scott T.
dc.contributor.author
Baas, Peter W.
dc.contributor.author
Morfini, Gerardo
dc.date.available
2018-12-14T17:25:25Z
dc.date.issued
2017-06
dc.identifier.citation
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
dc.identifier.issn
1460-2083
dc.identifier.uri
http://hdl.handle.net/11336/66499
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Oxford University Press
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Espastina
dc.subject
Transporte Axonal
dc.subject
Motores Moleculares
dc.subject
Ck2
dc.subject.classification
Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-10-23T18:08:58Z
dc.identifier.eissn
0964-6906
dc.journal.volume
26
dc.journal.number
12
dc.journal.pagination
2321-2334
dc.journal.pais
Reino Unido
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dc.journal.ciudad
Oxford
dc.description.fil
Fil: Leo, Lanfranco. Drexel University College of Medicine; Estados Unidos
dc.description.fil
Fil: Weissmann, Carina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Chicago; Estados Unidos
dc.description.fil
Fil: Burns, Matthew. University of Chicago; Estados Unidos
dc.description.fil
Fil: Kang, Minsu. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
dc.description.fil
Fil: Song, Yuyu. Marine Biological Laboratory; Estados Unidos. Yale University; Estados Unidos
dc.description.fil
Fil: Qiang, Liang. Drexel University College of Medicine; Estados Unidos
dc.description.fil
Fil: Brady, Scott T.. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
dc.description.fil
Fil: Baas, Peter W.. Drexel University College of Medicine; Estados Unidos
dc.description.fil
Fil: Morfini, Gerardo. University of Chicago; Estados Unidos. Marine Biological Laboratory; Estados Unidos
dc.journal.title
Human molecular genetics
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1093/hmg/ddx125
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/hmg/article/26/12/2321/3111723
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