Nerve Growth Factor. Fig. 1. (a) Schematic representation of the p-NGF monomer subunit highlighting structurally important residues. Bold, absolutely conserved residues for all NGF and NGF-related sequences. Squares, buried residues in the p-NGF subunit with a relative side-chain. The hexagons represent residues involved in the dimer interface as identified using computer imaging techniques. The side-chain of the residue participates in a hydrogen bond with either a side-chain or a main chain atom. The main chain hydrogen bonds involved in the p-sheet structure are displayed as arrows, pointing in the direction of the donor acceptor. The cysteine knot is shown as three solid lines linking six cysteine residues near the bottom of the molecule (From McDonald et al. (1991) Nature; with author's and publisher's permission). (b) Ribbon representation of the p-NGF dimer. The cyan and dark blue ribbons each represent a subunit. The Sg atom for each half-cystine residue is also shown drawn as a sphere. (From McDonald et al. (1991) Nature; with author's and publisher's permission). (c) Structure-based sequence alignment of the neurotrophins. Numbering refers to the sequence of mature human NGF. Positions are numbered from the first residue in each neurotrophin. Note that, because of differences in the lengths of the N-termini of the different neurotrophins, homologous positions in different molecules do not have equivalent numbering. Conserved residues are shaded and low sequence homology (boxes) and sequence of hairpin loops are represented. Dashes indicate gaps introduced for the sake of alignment. (From Skaper 2008. CNS Neurol Disord Drug Targets; with author's and publisher's permission.)




Nerve Growth Factor. Fig. 2. Neurotrophins and their receptors. The neurotrophins display specific interactions with the three Trk receptors: NGF binds TrkA, BDNF and NT-4 bind TrkB, and NT-3 binds TrkC. In some cellular contexts, NT-3 can also activate TrkA and TrkB albeit with less efficiency. All neurotrophins bind to and activate p75NTR. CR1-CR4, cysteine-rich motifs; C1/C2, cysteine-rich clusters; LRR1-3, leucine-rich repeats; Ig1/Ig2, immunoglobulin-like domains. (From Skaper 2008. Drug Targets. CNS Neurol Disord; with author's and publisher's permission.)

vesicles continue signaling via the Erk-CREB pathway (Grimes et al. 1996). These studies also indicate that the metalloproteinase MMP9 rapidly degrades and inactivates any remaining mNGF, which is not bound to the cognate receptor (TrkA) and rapidly internalized.

The above metabolic pathway involving plasmin for the maturation of NGF and MMP9 for its degradation has been pharmacologically validated in vivo, showing that the inhibition of tPA results in the brain accumulation of proNGF and, conversely, the inhibition of MMP9 in the accumulation of mNGF (Bruno and Cuello 2006). Fig. 4 illustrates the activity-dependent release of proNGF and its consequent conversion to mature NGF, binding to its cognate receptors and its eventual degradation in the extracellular space as well as the protease cascade and endogenous inhibitors.

The best-defined and most dramatic actions of the endogenously generated NGF are illustrated during embryonic stages and the early postnatal period. In brief, in in vitro conditions, the deprivation of NGF support leads to cell death of NGF-dependent embryonic neurons, typically small-size spinal cord primary sensory and ► sympathetic neurons. The early studies on the deprivation of NGF trophic support were performed by immunoneutra-lization with anti-NGF polyclonal antibodies and more recent studies were done with NGF knock-out (KO) or

NGF-deficient animal models. Mice lacking NGF or TrkA (KO models) do not survive beyond weeks after birth. The phenotype of NGF(—/—) or TrkA(—/—) mice is one of dramatic loss of NGF-dependent spinal cord sensory neurons and sympathetic neurons, but with a lesser effect on NGF-dependent forebrain neurons. However, mice carrying a single NGF allele have shown marked atrophy of forebrain cholinergic neurons of the nucleus basalis and medial septum. The most accepted view is that during development, the presence of NGF in defined target areas will attract axonal growth to the sites of termination (synapses in the CNS) and secure the eventual survival of NGF-dependent neurons (Sofroniew et al. 2001).

Many of the concepts derived from investigations on embryonic tissue have been applied to the adult nervous system. Thus, the concept of "target derived'' NGF support of CNS neurons in the adult brain was readily accepted. It was shown early on that axotomy of the septal-hippocampal cholinergic pathway in the adult brain resulted in the loss of the corresponding NGF sensitive cholinergic neurons. Their recovery by the application of NGF was interpreted as an indication of a similar NGF-dependency for neuronal survival in the adult and fully differentiated CNS. However, the substantial excito-toxic destruction of the target tissue (hippocampus),

Nerve Growth Factor. Fig. 3. Trk signaling pathways regulating survival and neurite growth in neuronal cells. Neurotrophin (NT) binding to Trk stimulates receptor transphosphorylation, resulting in the recruitment of a series of signaling proteins to docking sites on the receptor. These proteins include Shc, which activates Ras through Grb-2 and SOS, FRS-2, rAPS, SH2-B and CHK, which participate in activating MAPK, and PLC-g1 and CHK bind to phosphorylated Tyr 785. MAPK activity is also regulated through Raf, Rap 1, SHP-2, and PKCS . The MEK and MAPK pathway is thought to regulate neurite growth and survival. Trk activates Pl-3K through the RAS and the Gab-1/IRS-1/IRS-2 family of adapter proteins. Pl-3K activity stimulates the activities of PDK2, which in turn activate Akt. The targets of Pl-3K/Akt anti-apoptotic activity, including BAD, Forkhead, GSK-3, Bcl-2 lAP, and the p53 pathway involved in cell death. (From Kaplan and Miller 2000. Curr Opin Neurobiol; with author's and publisher's permission.)

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