Axon demyelination and degeneration in a zebrafish <i>spastizin</i> model of hereditary spastic paraplegia
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 <i>ZFYVE26</i> 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 <i>spastizin</i> mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.
Authors
- Selina André
- Patricia Scholz (ORCID: https://orcid.org/0000-0003-0761-9175)
- Martin C. Göpfert (ORCID: https://orcid.org/0000-0001-8201-5334)
- Roland Dosch (ORCID: https://orcid.org/0000-0001-9247-8586)
- Bart R. H. Geurten (ORCID: https://orcid.org/0000-0002-1816-3241)
- Torben Ruhwedel (ORCID: https://orcid.org/0000-0002-9535-9395)
- Christian Dullin (ORCID: https://orcid.org/0000-0003-4297-8077)
- Hauke B. Werner (ORCID: https://orcid.org/0000-0002-7710-5738)
- Jacob Engelmann (ORCID: https://orcid.org/0000-0002-1054-0938)
- Luisa Heyer
- Till Ischebeck (ORCID: https://orcid.org/0000-0003-0737-3822)
- Gudrun Kracht
- Vranda Garg (ORCID: https://orcid.org/0009-0000-4728-5400)
- Wiebke Möbius (ORCID: https://orcid.org/0000-0002-2902-7165)
Institutions
- Bielefeld University (DE)
- University of Münster (DE)
- Universitätsmedizin Göttingen (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- University of Göttingen (DE)
- University of Otago (NZ)
Publication Details
- Journal
- Open Biology
- Published
- 2024-11-01
- DOI
- https://doi.org/10.1098/rsob.240100
- Citations
- 4
- Primary Topic
- Hereditary Neurological Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.07
Funders
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft
- Georg-August-Universität Göttingen
- Studienstiftung des Deutschen Volkes
- Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften