PLEKHG5 is a guanine exchange factor (GEF) that primarily functions as an activator of the small GTPase RAB26, playing critical roles in neuronal and non-neuronal tissues. In motoneurons, PLEKHG5 regulates unconventional secretion of SOD1 through secretory autophagy, wherein it facilitates the fusion of autophagosomes with secretory lysosomal-related organelles and subsequent exocytosis 1. PLEKHG5 also controls autophagy more broadly and activates NF-κB signaling 2, with reported involvement in neuronal cell differentiation [UniProt reference]. Beyond the nervous system, PLEKHG5 regulates endothelial cell chemotaxis and migration during angiogenesis, and affects macrophage and osteoclast function [UniProt reference]. Mutations in PLEKHG5 cause autosomal recessive intermediate Charcot-Marie-Tooth disease (RI-CMT) 34, characterized by axonal neuropathy with distal motor and sensory involvement and abnormal myelin formation 5. PLEKHG5 mutations also cause distal hereditary motor neuron disease (dHMN4) 1. In the context of SOD1-linked ALS, reduced PLEKHG5 expression impairs mutant SOD1 secretion 1. Additionally, PLEKHG5 expression correlates with glioblastoma grade and patient survival, with elevated expression promoting tumor migration and invasion 6. Outside cancer, PLEKHG5 participates in autophagy regulation in endometriosis pathogenesis 7.