Cyclic AMP Signaling: A Molecular Determinant of Peripheral Nerve Regeneration

Knott, Eric P.; Assi, Mazen; Pearse, Damien D.

doi:10.1155/2014/651625

Cited by 29 publications

(21 citation statements)

References 66 publications

(88 reference statements)

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“…After PNS injury, SCs undergo a transdifferentiation process: they dedifferentiate, proliferate, and then differentiate back to a myelinating phenotype ( Jessen et al, 2015 ; Jessen and Mirsky, 2016 ). The transition between these stages relies heavily on cAMP signaling ( Knott et al, 2014 ). This process is less well defined within PSCs, which are clearly different from their myelinating counterparts.…”

Section: Discussionmentioning

confidence: 99%

ATP Released by Injured Neurons Activates Schwann Cells

Negro¹,

Bergamin²,

Rodella³

et al. 2016

Front. Cell. Neurosci.

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Injured nerve terminals of neuromuscular junctions (NMJs) can regenerate. This remarkable and complex response is governed by molecular signals that are exchanged among the cellular components of this synapse: motor axon nerve terminal (MAT), perisynaptic Schwann cells (PSCs), and muscle fiber. The nature of signals that govern MAT regeneration is ill-known. In the present study the spider toxin α-latrotoxin has been used as tool to investigate the mechanisms underlying peripheral neuroregeneration. Indeed this neurotoxin induces an acute, specific, localized and fully reversible damage of the presynaptic nerve terminal, and its action mimics the cascade of events that leads to nerve terminal degeneration in injured patients and in many neurodegenerative conditions. Here we provide evidence of an early release by degenerating neurons of adenosine triphosphate as alarm messenger, that contributes to the activation of a series of intracellular pathways within Schwann cells that are crucial for nerve regeneration: Ca2+, cAMP, ERK1/2, and CREB. These results contribute to define the cross-talk taking place among degenerating nerve terminals and PSCs, involved in the functional recovery of the NMJ.

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Section: Discussionmentioning

confidence: 99%

ATP Released by Injured Neurons Activates Schwann Cells

Negro¹,

Bergamin²,

Rodella³

et al. 2016

Front. Cell. Neurosci.

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show abstract

“…It is likely the donor axons that grew into the denervated nerve stump released agents such as neuregulin that promote the proliferation of the Schwann cells and their expression of regeneration associated genes. Those axons that made contact with Schwann cells were remyelinated by the Schwann cells (Figs 7 and 9 ), converting their gene expression from growth permissive to the myelinating phenotype [ 63 , 64 , 79 , 82 – 84 ]. Those that did not contact the Schwann cells likely sustained their expression of the regeneration associated genes, at least in part, via these same agents as well as agents that have not yet been identified.…”

Section: Discussionmentioning

confidence: 99%

Nerve Cross-Bridging to Enhance Nerve Regeneration in a Rat Model of Delayed Nerve Repair

et al. 2015

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There are currently no available options to promote nerve regeneration through chronically denervated distal nerve stumps. Here we used a rat model of delayed nerve repair asking of prior insertion of side-to-side cross-bridges between a donor tibial (TIB) nerve and a recipient denervated common peroneal (CP) nerve stump ameliorates poor nerve regeneration. First, numbers of retrogradely-labelled TIB neurons that grew axons into the nerve stump within three months, increased with the size of the perineurial windows opened in the TIB and CP nerves. Equal numbers of donor TIB axons regenerated into CP stumps either side of the cross-bridges, not being affected by target neurotrophic effects, or by removing the perineurium to insert 5-9 cross-bridges. Second, CP nerve stumps were coapted three months after inserting 0-9 cross-bridges and the number of 1) CP neurons that regenerated their axons within three months or 2) CP motor nerves that reinnervated the extensor digitorum longus (EDL) muscle within five months was determined by counting and motor unit number estimation (MUNE), respectively. We found that three but not more cross-bridges promoted the regeneration of axons and reinnervation of EDL muscle by all the CP motoneurons as compared to only 33% regenerating their axons when no cross-bridges were inserted. The same 3-fold increase in sensory nerve regeneration was found. In conclusion, side-to-side cross-bridges ameliorate poor regeneration after delayed nerve repair possibly by sustaining the growth-permissive state of denervated nerve stumps. Such autografts may be used in human repair surgery to improve outcomes after unavoidable delays.

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“…Particularly, in the FTD-network ( Fig 2 and S1 Fig ) oxidative stress was impacted due to impaired energetic metabolism [ 52 , 53 ] eliciting the activation of stress-responsive receptors, including Frizzled-4 ( FDZ4 ) and EGFR [ 54 – 64 ], and oxidative stress-inducible Serine/Threonine kinases CAMK2A , PRKACG , PRKACB , and PRKG1 [ 54 – 83 ]. Collaterally, these effectors may further induce neuron membrane potentiation, leading to apoptosis through activation of the MAPK-JNK signaling pathway [ 73 – 77 ] and Ca 2+ /cAMP metabolism deregulation [ 84 – 91 ]. Aberrant Ca 2+ /cAMP metabolism might lead to anomalous neuron potentials and further deficits in neuroprotection, neuron functioning, and survival [ 69 , 70 , 80 – 100 ].…”

Section: Resultsmentioning

confidence: 99%

“…Together with active cell damage, loss of neuroprotection may contribute to neural cell death. CAMK2A is connected to three different perturbed routes, involving cAMP and fatty acids metabolism [ 84 – 91 ], and including several mitochondrial proteins. The first route involves the adenylate cyclase ADCY3 , the phosphodiesterases PDE1A and PDE10A , and the GMP-deaminase GMPR ( Fig 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies highlighted the importance of intracellular levels of cAMP and cGMP for neuroprotection and neuron survival [ 84 – 91 ], and CAMK2 -dependent ADCY3 activation has been documented in mouse and rat brain [ 87 ]. Specifically, neuron regeneration, survival and synaptic plasticity seem to be enhanced by high intracellular levels of cAMP and cGMP [ 84 – 87 ], and antagonized by phosphodiesterases (PDEs) and myelin-associated glycoproteins (MAGs) [ 86 – 88 ]. In a recent study [ 88 ] PDE-dependent cAMP/cGMP control has been documented in Alzheimer’s disease (AD), depression and multiple sclerosis (MS), but not in FTD, to date.…”

Section: Discussionmentioning

confidence: 99%

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A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia

et al. 2017

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Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer’s disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.

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Cyclic AMP Signaling: A Molecular Determinant of Peripheral Nerve Regeneration

Cited by 29 publications

References 66 publications

ATP Released by Injured Neurons Activates Schwann Cells

ATP Released by Injured Neurons Activates Schwann Cells

Nerve Cross-Bridging to Enhance Nerve Regeneration in a Rat Model of Delayed Nerve Repair

A novel network analysis approach reveals DNA damage, oxidative stress and calcium/cAMP homeostasis-associated biomarkers in frontotemporal dementia

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