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Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by retrograde axonal degeneration that primarily affects long spinal neurons. The gene encoding spastin has a well‐established association with HSP, and protrudin is a known binding partner of spastin. Here, we demonstrate that the N‐terminal domain of protrudin mediates the interaction with spastin, which is responsible for neurite outgrowth. We show that spastin promotes protrudin‐dependent neurite outgrowth in PC12 cells. To further confirm these physiological functions in vivo, we microinjected zebrafish embryos with various protrudin/spastin mRNA and morpholinos. The results suggest that the spinal cord motor neuron axon outgrowth of zebrafish is regulated by the interaction between spastin and protrudin. In addition, the putative HSP‐associated protrudinG191V mutation was shown to alter the subcellular distribution …