title: Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation.
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.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Lanfranco
authors.initials: L
authors.lastname: Leo
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Carina
authors.initials: C
authors.lastname: Weissmann
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burns
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.|Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Minsu
authors.initials: M
authors.lastname: Kang
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA, USA.|Department of Genetics, School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.|Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Brady
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Baas
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.|Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Morfini
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000235:genetics* / Q000502:physiology; D047390:Casein Kinase II / Q000378:metabolism; D002478:Cells, Cultured; D049832:Decapodiformes; D004195:Disease Models, Animal; D005347:Fibroblasts; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism; D000074181:Spastin
chemical_list: D050505:Mutant Proteins; D020033:Protein Isoforms; D047390:Casein Kinase II; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human