ArticlePLoS biology2020
Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits.
Article in PLoS biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 60 citations in OpenAlex.
- The genetic overlap between schizophrenia and major depression with cognitive function.Molecular psychiatry · 2026Article
- Traffic Jams in the Brain: How Kinesin Dysfunction Shapes Neurodevelopmental Disorders.Current issues in molecular biology · 2026Review
- Post-Translational Modifications of Tubulin in Oocyte Maturation and Female Infertility.Cytoskeleton (Hoboken, N.J.) · 2026Review
- A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- The tubulin code in acute ischemic stroke: post-translational reprogramming of the neuronal cytoskeleton and implications for phase-specific neuroprotection.Frontiers in neuroscience · 2026Review
- Article
- CaMKIIβ-mediated Phosphorylation Enhances Protein Stability of Spastin to Promote Neurite Outgrowth.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Repeated Exposure to Sevoflurane in Neonatal Mice Induces Cognitive and Synaptic Impairments in a TTLL6-Mediated Tubulin Polyglutamylation Manner.CNS neuroscience & therapeutics · 2025Article
- Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation.Nature communications · 2025Article
- Emerging roles for tubulin PTMs in neuronal function and neurodegenerative disease.Current opinion in neurobiology · 2025Review
- Decoding the role of microtubules: a trafficking road for vesicle.Theranostics · 2025Review
- Effects of DeSUMOylated Spastin on AMPA Receptor Surface Delivery and Synaptic Function Are Enhanced by Phosphorylating at Ser210.Molecular neurobiology · 2024Article
- Spastin locally amplifies microtubule dynamics to pattern the axon for presynaptic cargo delivery.Current biology : CB · 2024Article
- Functional Inhibition of Katanin Affects Synaptic Plasticity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Connecting neurodevelopment to neurodegeneration: a spotlight on the role of kinesin superfamily protein 2A (KIF2A).Neural regeneration research · 2024Review
- Article
- Tubulin Cytoskeleton in Neurodegenerative Diseases-not Only Primary Tubulinopathies.Cellular and molecular neurobiology · 2023Review
- Spastin is required for human immunodeficiency virus-1 efficient replication through cooperation with the endosomal sorting complex required for transport (ESCRT) protein.Virologica Sinica · 2023Article
- Disruption of axonal transport in neurodegeneration.The Journal of clinical investigation · 2023Review
- Role of tubulin post-translational modifications in peripheral neuropathy.Experimental neurology · 2023Review
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.
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