Optic Nerve Regeneration and the Growth-Associated Protein GAP-43
The growth-associated protein GAP-43 participates in neuronal development and regeneration. In glaucoma, retinal ganglion cell axons become injured and will not regenerate to their target, causing blindness. During development, axons must navigate correctly to their proper destination, and this process must be repeated if neuronal regeneration is to occur. Receptors on axonal growth cone filopodia bind various factors, including neurotrophins, netrins, semaphorins, ephrins, and slits, which results in the growth cone turning in the direction of the target. When these factors bind, the signals are transmitted intracellularly, allowing GAP-43 and actin filaments to respond. Based on in vitro studies, it was suggested that GAP-43 binds directly to F-actin, but our most recent crosslinking studies in living neuroblastoma cells indicate that F-actin and GAP-43 act in the growing neuron without binding directly to each other.
Instead, the crucial role for GAP-43 appears to lie in its palmitoylation, which refers to the attachment of two palmitate chains near the N-terminus of the protein. This causes GAP-43 to enter lipid rafts, and particularly those that contain the acidic phospholipid phosphatidylinositol 4, 5-bisphosphate (PIP2). This appears to affect the way in which PIP2 controls actin dynamics, which provides for an indirect link between GAP-43 and actin.
It is known that protein palmitoylation is associated with neuronal growth, while inhibition of palmitoylation causes filopodia to collapse. We therefore are currently exploring ways of promoting the palmitoylation of GAP-43 as a means of promoting accurate neuronal regeneration. This is done using cultured retinal ganglion cells, neuroblastoma cells, and retinal explants. Retinal ganglion cell axons are injured as a means of simulating glaucoma. The effects of various trophic factors, including netrins and semaphorins, are tested for the ability to promote retinal ganglion cell regeneration and the palmitoylation of GAP-43.
References:
Denny JB. Molecular mechanisms, biological actions, and neuropharmacology of the growth-associated protein GAP-43. Curr Neuropharm 4:293-304, 2006.
Denny JB. Growth-associated protein of 43kDa (GAP-43) is cleaved nonprocessively by the 20S proteasome. Eur J Biochem 271:2480-2493, 2004.
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