Given the molecular functional and structural similarities among spastin, REEP1, and protrudin as well as the contributions of these proteins to the pathogenesis of HSP, we conclude that MCS formation and lipid transfer activity mediated by the protrudin-PDZD8 system are essential for endosomal maturation in the physiological setting. The gene discussed is ZFYVE27; the disease is hereditary spastic paraplegia.