SPG21 encodes maspardin, a cytosolic protein that functions as a RAB7A effector involved in endolysosomal trafficking and signaling. The protein localizes to endolysosomes through interaction with GTP-bound RAB7A and controls the subcellular positioning of this GTPase 1. SPG21 regulates mTORC1-mediated phosphorylation of the transcription factor TFEB, promoting its cytoplasmic retention and suppressing nuclear translocation 12. Loss of SPG21 function disrupts RAB7 localization from retromer-positive late endosomes to lysosomes, leading to enhanced lysosomal motility and altered TFEB signaling 2. The protein also interacts with aldehyde dehydrogenase ALDH16A1 and localizes to trans-Golgi network/late endosomal compartments 3. Mutations in SPG21 cause autosomal recessive spastic paraplegia type 21 (Mast syndrome), characterized by spastic paraparesis, dementia, thin corpus callosum, and white matter abnormalities 34. Disease-associated variants reduce SPG21 expression and disrupt endolysosomal localization in neurons, linking dysfunction to altered endolysosomal signaling pathways 1. Beyond neurological disease, SPG21 has been implicated in hepatocellular carcinoma progression and chemoresistance through TRPM7/JNK pathway activation 5.