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Hereditary Spastic Paraplegia (HSP) is a CNS disorder characterized by limb spasticity and movement impairment, due to degeneration of spinal motor neurons. A rare HSP form, associated with spastic gait, cerebellar atrophy and peripheral neuropathy, is caused by mutations in the GBA2 gene. Given that GBA2 regulates lipid homeostasis, its deficiency may affect neuronal development and function. To investigate this HSP form, we used gba2 zebrafish crispants and murine cerebellar neurons.
Since gba2 crispants showed reduced swimming ability, by using fluorescent transgenic zebrafish lines we performed volumetric analysis and found cerebellar atrophy, together with altered motor neuron outgrowth and aberrant axonal branching, leading to spinal nerves defects. Similarly, confocal imaging of GBA2-inhibited murine cerebellar neurons revealed defective axonal growth, evidenced by Sholl analysis, and synaptic disorganization, while calcium signaling dynamics confirmed hampered neuronal activity.