Axon Demyelination and Degeneration in a Zebrafish Model of Hereditary Spastic Paraplegia

Overview

Journal Open Biol

Specialties Biology
Cell Biology
Molecular Biology

Date 2024 Nov 6

PMID 39503232

Authors

Vranda Garg

Selina Andre

Luisa Heyer

Gudrun Kracht

Torben Ruhwedel

Patricia Scholz

Till Ischebeck

Hauke B Werner

Christian Dullin

Jacob Engelmann

Wiebke Mobius

Martin C Gopfert

Roland Dosch

Bart R H Geurten

Affiliations

Soon will be listed here.

Abstract

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish. This disorder is caused in humans by mutations in the gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of large motor neurons. Motor neuron degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.

References

Tesson C, Koht J, Stevanin G . Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum Genet. 2015; 134(6):511-38. PMC: 4424374. DOI: 10.1007/s00439-015-1536-7. View

Muller U, Stamhuis E, Videler J . Hydrodynamics of unsteady fish swimming and the effects of body size: comparing the flow fields of fish larvae and adults. J Exp Biol. 1999; 203(Pt 2):193-206. DOI: 10.1242/jeb.203.2.193. View

Garg V, Geurten B . Diving deep: zebrafish models in motor neuron degeneration research. Front Neurosci. 2024; 18:1424025. PMC: 11222423. DOI: 10.3389/fnins.2024.1424025. View

Martin E, Yanicostas C, Rastetter A, Naini S, Maouedj A, Kabashi E . Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish. Neurobiol Dis. 2012; 48(3):299-308. DOI: 10.1016/j.nbd.2012.07.003. View

Klebe S, Stevanin G, Depienne C . Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting. Rev Neurol (Paris). 2015; 171(6-7):505-30. DOI: 10.1016/j.neurol.2015.02.017. View

Boutry M, Pierga A, Matusiak R, Branchu J, Houllegatte M, Ibrahim Y . Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis. Commun Biol. 2019; 2:380. PMC: 6797781. DOI: 10.1038/s42003-019-0615-z. View

Hsu S, Lu Y, Tsai Y, Chao H, Fuh J, Liao Y . Investigating ZFYVE26 mutations in a Taiwanese cohort with hereditary spastic paraplegia. J Formos Med Assoc. 2021; 121(1 Pt 1):126-133. DOI: 10.1016/j.jfma.2021.02.005. View

Slabicki M, Theis M, Krastev D, Samsonov S, Mundwiller E, Junqueira M . A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. PLoS Biol. 2010; 8(6):e1000408. PMC: 2893954. DOI: 10.1371/journal.pbio.1000408. View

Chang J, Lee S, Blackstone C . Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. J Clin Invest. 2014; 124(12):5249-62. PMC: 4348974. DOI: 10.1172/JCI77598. View

10.

Vance J . Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech. 2012; 5(6):746-55. PMC: 3484857. DOI: 10.1242/dmm.010124. View

11.

Arnold G . Rheotropism in fishes. Biol Rev Camb Philos Soc. 1974; 49(4):515-76. DOI: 10.1111/j.1469-185x.1974.tb01173.x. View

12.

Harding A . Hereditary spastic paraplegias. Semin Neurol. 1993; 13(4):333-6. DOI: 10.1055/s-2008-1041143. View

13.

Stavoe A, Holzbaur E . Autophagy in Neurons. Annu Rev Cell Dev Biol. 2019; 35:477-500. PMC: 6996145. DOI: 10.1146/annurev-cellbio-100818-125242. View

14.

Sagona A, Nezis I, Pedersen N, Liestol K, Poulton J, Rusten T . PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody. Nat Cell Biol. 2010; 12(4):362-71. DOI: 10.1038/ncb2036. View

15.

Kanagaraj P, Gautier-Stein A, Riedel D, Schomburg C, Cerda J, Vollack N . Souffle/Spastizin controls secretory vesicle maturation during zebrafish oogenesis. PLoS Genet. 2014; 10(6):e1004449. PMC: 4072560. DOI: 10.1371/journal.pgen.1004449. View

16.

Hanein S, Martin E, Boukhris A, Byrne P, Goizet C, Hamri A . Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet. 2008; 82(4):992-1002. PMC: 2427184. DOI: 10.1016/j.ajhg.2008.03.004. View

17.

Blackstone C, OKane C, Reid E . Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci. 2010; 12(1):31-42. PMC: 5584382. DOI: 10.1038/nrn2946. View

18.

Vantaggiato C, Panzeri E, Castelli M, Citterio A, Arnoldi A, Santorelli F . ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis. Autophagy. 2018; 15(1):34-57. PMC: 6287682. DOI: 10.1080/15548627.2018.1507438. View

19.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

20.

Krause M, Regen S . The structural role of cholesterol in cell membranes: from condensed bilayers to lipid rafts. Acc Chem Res. 2014; 47(12):3512-21. DOI: 10.1021/ar500260t. View