TY - JOUR T1 - Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway JF - The Journal of Neuroscience JO - J. Neurosci. SP - 6156 LP - 6166 DO - 10.1523/JNEUROSCI.1017-05.2005 VL - 25 IS - 26 AU - Zhe-Yu Chen AU - Alessandro Ieraci AU - Henry Teng AU - Henning Dall AU - Chui-Xiang Meng AU - Daniel G. Herrera AU - Anders Nykjaer AU - Barbara L. Hempstead AU - Francis S. Lee Y1 - 2005/06/29 UR - http://www.jneurosci.org/content/25/26/6156.abstract N2 - Brain-derived neurotrophic factor (BDNF), after activity-dependent secretion from neurons, modulates critical nervous system functions. Recently, a variant in the human bdnf gene, resulting in a valine to methionine substitution in the prodomain, has been shown to lead to defective regulated secretion from neurons and memory impairment. Here, we report a novel function for a Vps10p domain protein, sortilin, in controlling BDNF sorting to the regulated secretory pathway. Sortilin interacts specifically with BDNF in a region encompassing the methionine substitution and colocalizes with BDNF in secretory granules in neurons. A truncated form of sortilin causes BDNF missorting to the constitutive secretory pathway without affecting neurotrophin-4 (NT-4) secretion. In addition, sortilin small interfering RNA introduced into primary neurons also led to BDNF missorting from the regulated to the constitutive secretory pathway. Together, these data suggest a mechanism to understand the defect associated with variant BDNF and provide a framework, based on divergent presynaptic regulation of sorting to secretory pathways, to explain how two ligands for tropomyosin-related kinase B, BDNF and NT-4, can mediate diverse biological responses. ER -