As indicated earlier, mature and biologically active NGF is the immediate product of a larger precursor protein, proNGF. Western blot analysis reveal that the predominant form of NGF in the adult CNS is proNGF (Fahnestock et al. 2001). It has been proposed that proNGF can be cleaved intracellularly by the action of furin converting proNGF into NGF. However, the degree to which the "conversion" of proNGF into mNGF takes place intra or extracellularly is debatable. Studies with transfected cell lines have shown that a furin-resistant form of proNGF can be released into the extracellular space and induce cell death via the activation of p75NTR (Lee et al. 2001), possibly when TrkA levels are low. Cell biology studies indicate that the secretion of NGF is activity-dependent. Ex-vivo studies with superfused cerebral cortex tissue of adult rats have revealed that proNGF is the molecular form released in an activity-dependent manner, following depolarization or neurotransmitter stimulation (Bruno and Cuello 2006). These studies also indicate that in the adult and fully differentiated nervous system, the conversion of proNGF occurs in the extracellular space by the coordinated action of plasminogen and tissue plas-minogen activator (tPA) producing plasmin which converts proNGF into mNGF (Bruno and Cuello 2006). Mature NGF and corresponding activated TrkA receptor are internalized in endosomal vesicles, which are transported retrogradely by axonal processes from nerve terminals to perinuclear regions of neurons, where the
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