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Activity-mediated secretion of progranulin-containing granules Petoukhov, Eugenia


Progranulin (PGRN) is a multi-functional, secreted growth factor expressed in a variety of tissues throughout the body. In the central nervous system (CNS), PGRN is expressed in microglia as well as in a number of neuronal populations and has been shown to promote neuronal survival, enhance neurite outgrowth and regulate inflammation and development. Mutations in the progranulin (GRN) gene have been identified as a major cause of autosomal dominant frontotemporal dementia (FTD) with tau-negative inclusions. The majority of GRN mutations result in the production of a null allele and reduced PGRN expression. However, the normal functions of PGRN in the CNS remain poorly understood. Our study examines the secretion characteristics of PGRN in neurons. To study the secretion of PGRN from axons and dendrites, we have fused a pH-sensitive optical reporter of exocytosis, superecliptic pHluorin, to PGRN (PGRN-SEP). We demonstrate that activity enhances the secretion of PGRN from axons and dendrites with different temporal profiles of secretion. We show, using calcium blockers and calcium-free media, that activity-mediated secretion of PGRN requires Ca²⁺ entry via voltage-gated calcium channels (VGCC). We postulate that activity-dependent secretion of PGRN may enhance the formation and maturation of synapses as treatment of hippocampal neurons with recombinant PGRN results in an increase in synapse density.

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