A Shift from a Pivotal to Supporting Role for the Growth-Associated Protein (GAP-43) in the Coordination of Axonal Structural and Functional Plasticity

Abstract

In a number of animal species, the growth-associated protein (GAP), GAP-43 (aka: F1, neuromodulin, B-50, G50, pp46), has been implicated in the regulation of presynaptic vesicular function and axonal growth and plasticity via its own biochemical properties and interactions with a number of other presynaptic proteins. Changes in the expression of GAP-43 mRNA or distribution of the protein coincide with axonal outgrowth as a consequence of neuronal damage and presynaptic rearrangement that would occur following instances of elevated patterned neural activity including memory formation and development. While functional enhancement in GAP-43 mRNA and/or protein activity has historically been hypothesized as a central mediator of axonal neuroplastic and regenerative responses in the central nervous system, it does not appear to be the crucial substrate sufficient for driving these responses. This review explores the historical discovery of GAP-43 (and associated monikers), its transcriptional, post-transcriptional and post-translational regulation and current understanding of protein interactions and regulation with respect to its role in axonal function. While GAP-43 itself appears to have moved from a pivotal to a supporting factor, there is no doubt that investigations into its functions have provided a clearer understanding of the biochemical underpinnings of axonal plasticity.

Small Fibre Neuropathy in Parkinson’s Disease: Comparison of Skin Biopsies from the More Affected and Less Affected Sides

“…We also demonstrated increased MAL, TNFL/Length and TNFL/Area on the more affected compared to less affected side. These markers are indicative of nerve fibre regeneration [11][12][13][14][15]. Thus we demonstrate both increased neurodegeneration and increased regeneration on the more affected compared to less affected side.…”

“…In our studies in patients with PD, also using PGP9.5, we have shown a reduction in IENFD and corneal small nerve fibre density and related it to autonomic dysfunction and the perception of affective touch [9,10]. Recently, we have demonstrated the added value of applying more refined quantification of nerve fibre morphology which includes quantifying mean dendrite length (MDL) [11] and total nerve fibre length (TNFL) after immunostaining for growth associated protein-43 (GAP-43) [12], a marker of regenerating nerves in both experimental and human studies [13][14][15]. The MDL acronym was adopted from the literature, we now use a correct term MAL (mean axonal length) [16].…”

Handling has an anxiolytic effect that is not affected by the inhibition of the protein kinase C pathway in adult prenatal undernourished male rat offspring

“…A previous report mentioned that grooming with a soft brush followed by physical EE in rat pups improved their spatial learning and memory ability through restoration of the level of GAP‐43 in the hippocampus, and this pathway had been disturbed by maternal restraint stress during pregnancy . The Ca 2+ ‐dependent PKC phosphorylation of GAP‐43 is associated with synaptic plasticity and neurite outgrowth, and GAP‐43 phosphorylation was increased following long‐term potentiation induction and affected memory function . Hence, neonatal handling followed by physical EE may restore cognitive functions through PKC signaling.…”

“…18 The Ca 2+ -dependent PKC phosphorylation of GAP-43 is associated with synaptic plasticity and neurite outgrowth, and GAP-43 phosphorylation was increased following long-term potentiation induction and affected memory function. 30 Hence, neonatal handling followed by physical EE may restore cognitive functions through PKC signaling. Actually, EE inhibited the decrease in spine densities of the hippocampal CA1 neurons concomitantly with a partial reduction of anxiety and damage in learning and memory of prenatal-stressed offspring in rats.…”

The Interplay between Retinal Pathways of Cholesterol Output and Its Effects on Mouse Retina

“…In turn, these potential effects on the cilia can be compensated, fully or in part, by an increased expression of the proteins involved in rhodopsin traffic (ASAP1 and PI4KA), protein ubiquitination (CUL1, STUB1, and UCHL5) as well as the photoreceptor gene transcription (NR2E3 and RORβ) [68][69][70][71][72][73][74][75][76]. In addition, impaired ERG function could reflect a balance between the negative (decreased expression GPM6A and RAB4B) and positive (increased expression of GAP43 and KCTD8) effects on synaptic processes [77][78][79][80]. Inflammation may lead to the photoreceptor loss and thereby affect the ERG as well.…”