AP5Z1 encodes the zeta-1 subunit of the AP-5 adaptor protein complex, a component of the intracellular trafficking machinery with multiple critical functions. As part of the AP-5 complex, AP5Z1 participates in endosomal transport and lysosomal pathway maintenance 1. The protein localizes to late endosomes and the Golgi apparatus 1 and plays a role in regulating autophagy and lysosomal organization 2. Biallelic AP5Z1 mutations cause spastic paraplegia 48 (SPG48), a neurodegenerative disorder characterized by progressive lower limb spasticity and pyramidal weakness 34. Disease pathogenesis involves impaired mitochondrial dynamics, with reduced mitochondrial length and density in axons, decreased membrane potential, and abnormal balance between mitochondrial fission and fusion 5. Additionally, AP5Z1 disruption sensitizes the non-canonical inflammasome pathway, contributing to neuro-inflammation 6. Beyond neurodegeneration, AP5Z1 has oncogenic roles in hepatocellular carcinoma, where elevated expression promotes cell growth and suppresses apoptosis by ubiquitinating PTEN and modulating the PI3K/Akt/mTOR pathway 2. AP5Z1 variants also cause hereditary macular dystrophy affecting the retinal pigment epithelium 1, highlighting tissue-specific importance of AP-5-mediated lysosomal function.