Modeling Hereditary Spastic Paraplegia (HSP) in Zebrafish

Zebrafish significantly contribute to the study of hereditary spastic paraplegia (HSP) by providing a genetic animal model, amenable to live imaging, for addressing the cellular mechanisms by which known human mutations in spastic paraplegia genes lead to pathology. Loss-of-function studies, using antisense morpholinos of several zebrafish homologs of HSP genes, all show a common phenotype: shortened spinal motor neuron axons, abnormal branching, and reduced motility. These phenotypes are, in the majority of the cases, rescued by the human wild-type mRNA, but not the mutated forms. More importantly, zebrafish have contributed to establishing a novel functional link between the SPG3a gene atlastin and regulation of the bone morphogenetic protein (BMP) signaling activity in motor neurons. Atlastin regulation of endocytosis and trafficking of the BMP receptor BMPR1 provided evidence for the role of signaling pathways in motor neurodegeneration and new possible targets for novel therapeutic approaches.