The Role of Spastin in Axon Biology

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2022 Jul 22

PMID 35865632

Authors

Ana Catarina Costa

Monica Mendes Sousa

Affiliations

Soon will be listed here.

Abstract

Neurons are highly polarized cells with elaborate shapes that allow them to perform their function. In neurons, microtubule organization-length, density, and dynamics-are essential for the establishment of polarity, growth, and transport. A mounting body of evidence shows that modulation of the microtubule cytoskeleton by microtubule-associated proteins fine tunes key aspects of neuronal cell biology. In this respect, microtubule severing enzymes-spastin, katanin and fidgetin-a group of microtubule-associated proteins that bind to and generate internal breaks in the microtubule lattice, are emerging as key modulators of the microtubule cytoskeleton in different model systems. In this review, we provide an integrative view on the latest research demonstrating the key role of spastin in neurons, specifically in the context of axonal cell biology. We focus on the function of spastin in the regulation of microtubule organization, and axonal transport, that underlie its importance in the intricate control of axon growth, branching and regeneration.

Citing Articles

Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation.

Sebastien M, Paquette A, Prowse E, Hendricks A, Brouhard G Nat Commun. 2025; 16(1):1749.

PMID: 39966472 PMC: 11836384. DOI: 10.1038/s41467-025-56951-2.

Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment.

Sardina F, Polverino F, Valentini S, Carsetti C, Falvo E, Tisci G Cell Death Discov. 2025; 11(1):53.

PMID: 39920118 PMC: 11806007. DOI: 10.1038/s41420-025-02333-y.

From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.

Degoutin M, Angelini C, Bar C, El Khedoud W, Barnerias C, Boulariah-Hadjou R Eur J Neurol. 2024; 32(1):e70025.

PMID: 39731306 PMC: 11680745. DOI: 10.1111/ene.70025.

Fidgetin binds spastin to attenuate the microtubule-severing activity.

Sun Y, Ramakrishnan S, Lai X, Wu R, Dong Z, Qiang L Biochim Biophys Acta Mol Cell Res. 2024; 1872(2):119890.

PMID: 39681249 PMC: 11747943. DOI: 10.1016/j.bbamcr.2024.119890.

Tubulin glutamylation regulates axon guidance via the selective tuning of microtubule-severing enzymes.

Ten Martin D, Jardin N, Vougny J, Giudicelli F, Gasmi L, Berbee N EMBO J. 2024; 44(1):107-140.

PMID: 39613968 PMC: 11695996. DOI: 10.1038/s44318-024-00307-x.

References

Solowska J, Rao A, Baas P . Truncating mutations of associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin. Mol Biol Cell. 2017; 28(13):1728-1737. PMC: 5491181. DOI: 10.1091/mbc.E17-01-0047. View

Abrahamsen G, Fan Y, Matigian N, Wali G, Bellette B, Sutharsan R . A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations. Dis Model Mech. 2012; 6(2):489-502. PMC: 3597030. DOI: 10.1242/dmm.010884. View

Lindeboom J, Nakamura M, Saltini M, Hibbel A, Walia A, Ketelaar T . CLASP stabilization of plus ends created by severing promotes microtubule creation and reorientation. J Cell Biol. 2018; 218(1):190-205. PMC: 6314540. DOI: 10.1083/jcb.201805047. View

Petrova V, Pearson C, Ching J, Tribble J, Solano A, Yang Y . Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat Commun. 2020; 11(1):5614. PMC: 7645621. DOI: 10.1038/s41467-020-19436-y. View

Guedes-Dias P, Nirschl J, Abreu N, Tokito M, Janke C, Magiera M . Kinesin-3 Responds to Local Microtubule Dynamics to Target Synaptic Cargo Delivery to the Presynapse. Curr Biol. 2019; 29(2):268-282.e8. PMC: 6342647. DOI: 10.1016/j.cub.2018.11.065. View

Baas P, Black M . Individual microtubules in the axon consist of domains that differ in both composition and stability. J Cell Biol. 1990; 111(2):495-509. PMC: 2116207. DOI: 10.1083/jcb.111.2.495. View

Leo L, Yu W, DRozario M, Waddell E, Marenda D, Baird M . Vertebrate Fidgetin Restrains Axonal Growth by Severing Labile Domains of Microtubules. Cell Rep. 2015; 12(11):1723-30. PMC: 4837332. DOI: 10.1016/j.celrep.2015.08.017. View

Shida T, Cueva J, Xu Z, Goodman M, Nachury M . The major alpha-tubulin K40 acetyltransferase alphaTAT1 promotes rapid ciliogenesis and efficient mechanosensation. Proc Natl Acad Sci U S A. 2010; 107(50):21517-22. PMC: 3003046. DOI: 10.1073/pnas.1013728107. View

Leo L, Weissmann C, Burns M, Kang M, Song Y, Qiang L . Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation. Hum Mol Genet. 2017; 26(12):2321-2334. PMC: 6075366. DOI: 10.1093/hmg/ddx125. View

10.

Sulimenko V, Hajkova Z, Klebanovych A, Draber P . Regulation of microtubule nucleation mediated by γ-tubulin complexes. Protoplasma. 2017; 254(3):1187-1199. DOI: 10.1007/s00709-016-1070-z. View

11.

Terasaki M, Chen L, Fujiwara K . Microtubules and the endoplasmic reticulum are highly interdependent structures. J Cell Biol. 1986; 103(4):1557-68. PMC: 2114338. DOI: 10.1083/jcb.103.4.1557. View

12.

Sherwood N, Sun Q, Xue M, Zhang B, Zinn K . Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function. PLoS Biol. 2004; 2(12):e429. PMC: 532392. DOI: 10.1371/journal.pbio.0020429. View

13.

Cho Y, Sloutsky R, Naegle K, Cavalli V . Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell. 2013; 155(4):894-908. PMC: 3987749. DOI: 10.1016/j.cell.2013.10.004. View

14.

Wali G, Sutharsan R, Fan Y, Stewart R, Tello Velasquez J, Sue C . Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia. Sci Rep. 2016; 6:27004. PMC: 4882512. DOI: 10.1038/srep27004. View

15.

Jiang Y, Oblinger M . Differential regulation of beta III and other tubulin genes during peripheral and central neuron development. J Cell Sci. 1992; 103 ( Pt 3):643-51. DOI: 10.1242/jcs.103.3.643. View

16.

Akhmanova A, Kapitein L . Mechanisms of microtubule organization in differentiated animal cells. Nat Rev Mol Cell Biol. 2022; 23(8):541-558. DOI: 10.1038/s41580-022-00473-y. View

17.

LHernault S, Rosenbaum J . Chlamydomonas alpha-tubulin is posttranslationally modified in the flagella during flagellar assembly. J Cell Biol. 1983; 97(1):258-63. PMC: 2112491. DOI: 10.1083/jcb.97.1.258. View

18.

Ikegami K, Mukai M, Tsuchida J, Heier R, MacGregor G, Setou M . TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites. J Biol Chem. 2006; 281(41):30707-16. PMC: 3049811. DOI: 10.1074/jbc.M603984200. View

19.

Gaetz M . The neurophysiology of brain injury. Clin Neurophysiol. 2004; 115(1):4-18. DOI: 10.1016/s1388-2457(03)00258-x. View

20.

Denton K, Lei L, Grenier J, Rodionov V, Blackstone C, Li X . Loss of spastin function results in disease-specific axonal defects in human pluripotent stem cell-based models of hereditary spastic paraplegia. Stem Cells. 2013; 32(2):414-23. PMC: 3947148. DOI: 10.1002/stem.1569. View