Axon demyelination and degeneration in a zebrafish spastizin model of hereditary spastic paraplegia
biorxiv(2024)
摘要
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 little understood. We studied the pathogenesis of one form of HSP known as spastic paraplegia 15 (SPG15). This disorder is caused by mutations in the ZFYVE26 gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of Mauthner (M)-cells. M-cell degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the spastizin mutants. Our findings reveal that the mutation not only compromises axonal integrity but also affects the structural molecules of the myelin sheath, laying the foundation for degeneration and advancing our understanding of the intricate mechanisms underlying HSPs.
### Competing Interest Statement
The authors have declared no competing interest.
* HSP
: Hereditary spastic paraplegia
SPG15
: Spastic paraplegia 15
M-cell
: Mauthner cell
ER
: Endoplasmic reticulum
T7E1
: T7 Endonuclease 1
FPS
: Frames per second
LACE
: Limbless animal traCkEr
GC-MS
: Gas chromatography-mass spectrometry
CT
: Computed tomography
2-D
: 2-Dimensional
NMO
: Neuromyelitis optica
EAE
: Experimental autoimmune encephalomyelitis
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