REEP2 (receptor accessory protein 2) is a membrane-shaping protein primarily required for endoplasmic reticulum (ER) network formation and remodeling 12. REEP2 belongs to the REEP1-4 subfamily and generates membrane curvature to create a unique ER-derived vesicular compartment that cycles back to the ER via atlastin-mediated fusion 1. The protein exhibits tissue-specific expression, being preferentially found in neuronal tissues (brain, spinal cord) and neuronal-like exocytotic tissues (testes, pituitary, adrenal gland) 3. Under DNA damage conditions, REEP2 expression is transcriptionally upregulated by p53, promoting ER tubular extension and facilitating ER-mitochondria contacts that enhance calcium transfer and apoptosis 4. Disease-causing mutations in REEP2 lead to hereditary spastic paraplegia (SPG72) through both autosomal dominant and recessive mechanisms 56. Dominant mutations like p.Val36Glu act through a dominant-negative effect, preventing wild-type REEP2 membrane association, while recessive mutations like p.Phe72Tyr reduce membrane affinity 5. The neuronal-specific expression pattern of REEP2 aligns with the motor neuron degeneration observed in SPG72 patients 3.