ArticleHuman molecular genetics2017
Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 42 citations in OpenAlex.
- Microtubules in Spinal Cord Injury: From Cytoskeletal Dysregulation to Therapeutic Regeneration.Journal of neurochemistry · 2026Review
- Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology.Cell reports · 2026Article
- UCHL1-Mediated Spastin Degradation Regulates Microtubule Severing and Hippocampal Neurite Outgrowth.Journal of molecular neuroscience : MN · 2025Article
- Unraveling Isoform Complexity: The Roles of M1- and M87-Spastin in Spastic Paraplegia 4 (SPG4).Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment.Cell death discovery · 2025Article
- Spastin accumulation and motor neuron defects caused by a novel SPAST splice site mutation.Journal of translational medicine · 2024Article
- Article
- Hereditary spastic paraplegia: Novel insights into the pathogenesis and management.SAGE open medicine · 2024Review
- Article
- Editorial: Kinase/phosphatase signaling and axonal function in health and disease.Frontiers in cellular neuroscience · 2023Article
- FBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia.Cell & bioscience · 2022Article
- Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice.Human molecular genetics · 2022Article
- High-Resolution Imaging of Mitochondria and Mitochondrial Nucleoids in Differentiated SH-SY5Y Cells.Methods in molecular biology (Clifton, N.J.) · 2022Article
- The Role of Spastin in Axon Biology.Frontiers in cell and developmental biology · 2022Review
- Molecular and cellular mechanisms of spastin in neural development and disease (Review).International journal of molecular medicine · 2021Review
- Therapeutic Strategies for MutantBrain sciences · 2021Review
- The Mammalian Family of Katanin Microtubule-Severing Enzymes.Frontiers in cell and developmental biology · 2021Review
- Interplay of the nuclear envelope with chromatin in physiology and pathology.Nucleus (Austin, Tex.) · 2020Review
- Spastin mutations impair coordination between lipid droplet dispersion and reticulum.PLoS genetics · 2020Article
- Anterograde Axonal Transport in Neuronal Homeostasis and Disease.Frontiers in molecular neuroscience · 2020Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.