Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
| Autor: | Lanfranco Leo, Scott T. Brady, Minsu Kang, Carina Weissmann, Matthew R. Burns, Liang Qiang, Gerardo Morfini, Peter W. Baas, Yuyu Song |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Spastin Mutant MOTORES MOLECULARES medicine.disease_cause Axonal Transport Microtubules purl.org/becyt/ford/1 [https] 0302 clinical medicine Protein Isoforms Casein Kinase II Cells Cultured Genetics (clinical) Adenosine Triphosphatases Motor Neurons Mutation Decapodiformes Articles General Medicine Protein Transport Biochemistry Casein kinase 2 CIENCIAS NATURALES Y EXACTAS Intracellular Gene isoform Hereditary spastic paraplegia CK2 Otras Ciencias Biológicas TRANSPORTE AXONAL Biology Ciencias Biológicas 03 medical and health sciences Microtubule Genetics medicine Animals Humans purl.org/becyt/ford/1.6 [https] Molecular Biology Spastic Paraplegia Hereditary Fibroblasts medicine.disease ESPASTINA Rats Disease Models Animal 030104 developmental biology Mutant Proteins 030217 neurology & neurosurgery |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddx125 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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