Axon demyelination and degeneration in a zebrafishspastizinmodel of hereditary spastic paraplegia

Abstract

AbstractHereditary 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 theZFYVE26gene, 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 thespastizinmutants. 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.