Multiple functions of the ER-resident VAP and its extracellular role in neural development and disease.

VAP (VAMP-associated protein) is a type II integral membrane protein of the endoplasmic reticulum (ER), and its N-terminal major sperm protein (MSP) domain faces the cytoplasmic side. VAP functions as a tethering molecule at the membrane contact sites between the ER and intracellular organelles and regulates a wide variety of cellular functions, including lipid transport, membrane trafficking, microtubule reorganization and unfolded protein response. VAP-point mutations in human vapb are strongly associated with amyotrophic lateral sclerosis. Importantly, the MSP domain of VAP is cleaved, secreted and interacts with the axon growth cone guidance receptors (Eph, Robo, Lar), suggesting that VAP could function as a circulating hormone similar to the Caenorhabditis elegans MSP protein. In this review, we discuss not only the intracellular functions of VAP but also the recently discovered extracellular functions and their implications for neurodegenerative disease.