Journal article
Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
Human molecular genetics, v 26(12), pp 2321-2334
15 Jun 2017
PMID: 28398512
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation
- Creators
- Lanfranco Leo - Drexel UniversityCarina Weissmann - University of Illinois at ChicagoMatthew Burns - University of Illinois at ChicagoMinsu Kang - University of Illinois at ChicagoYuyu Song - Marine Biological LaboratoryLiang Qiang - Drexel UniversityScott T. Brady - University of Illinois at ChicagoPeter W. Baas - Drexel UniversityGerardo Morfini - University of Illinois at Chicago
- Publication Details
- Human molecular genetics, v 26(12), pp 2321-2334
- Publisher
- Oxford Univ Press
- Number of pages
- 14
- Grant note
- NS066942A; NS096642; NS023868; NS041170; NS28785 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Tom Wahlig Foundation R21NS096642 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Pennsylvania Department of Health CURE grants through Drexel University College of Medicine Dean's Fellowship for Excellence in Collaborative Research Training from Drexel University's Graduate School
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000402819800012
- Scopus ID
- 2-s2.0-85021627957
- Other Identifier
- 991019168445604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity