SH3GL2 (endophilin A1) is a membrane-binding protein with primary roles in synaptic vesicle endocytosis and neuronal signaling. Structurally, it contains an SH3 domain and recruits proteins to high-curvature membranes, mediating fast endophilin-mediated endocytosis (FEME) through dynamin-dependent mechanisms 1. SH3GL2 is required for BDNF-dependent dendrite outgrowth and couples activity-induced calcium influx to synaptic autophagy in dopaminergic neurons 2. At the mechanistic level, SH3GL2 functions in BDNF-NTRK2 early endocytic trafficking and can translocate to mitochondria where it regulates mitochondrial fusion and oxidative stress responses 3. Notably, a Parkinson disease-risk mutation in the disordered loop reduces SH3GL2 flexibility and nanodomain mobility, blocking stimulation-induced autophagy critical for neuronal survival 2. Clinically, SH3GL2 acts as a tumor suppressor. Frequent deletion and promoter methylation occur in vulvar squamous cell carcinoma, correlating with TNM stage and HPV infection 4, and in breast cancer where loss associates with increased metastases 3. In head and neck carcinoma, SH3GL2 inactivation enables EGFR overexpression and predicts poor survival 5. SH3GL2 dysfunction contributes to Parkinson disease pathogenesis through disrupted synaptic vesicle endocytosis 6. SNP rs1049430 in the 3'-UTR affects mRNA stability and serves as a prognostic marker 7.