Axonal fusion: An alternative and efficient mechanism of nerve repair

Neumann, Brent; Linton, Casey; Giordano-Santini, Rosina; Hilliard, Massimo A.

doi:10.1016/j.pneurobio.2018.11.004

Cited by 24 publications

(18 citation statements)

References 202 publications

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“…Besides, it would also be interesting to know the details on how SIRT2 inhibition promotes this improvement in functional recovery since we have not observed a significant increase in the number of regenerating axons. Recovery of function after nerve injury depends on different aspects aside from an accelerated axonal regeneration; on newly axons elongating, on branching/sprouting from the injury site or close to the denervated territory, on modulating membrane conductive properties [40], on changes in the motor unit size, and also on axonal fusion events [41], on accelerated maturation of NMJ, regenerated or surviving axons. Further research would clarify whether motor units are enlarged or axons are reinforced after nerve damage in SIRT2 KOs.…”

Section: Discussionmentioning

confidence: 99%

SIRT2 Inhibition Improves Functional Motor Recovery After Peripheral Nerve Injury

Leiva-Rodríguez

Casas

2020

Neurotherapeutics

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Sirtuin-2 (Sirt2) is a member of the NAD (+)-dependent protein deacetylase family involved in neuroprotection, cellular metabolism, homeostasis, and stress responses after injury of the nervous system. So far, no data have been published describing the role of SIRT2 in motor functional recovery after damage. We found that SIRT2 expression and deacetylase activity were increased within motoneurons after axotomy. To shed light onto the biological relevance of this change, we combined in vitro and in vivo models with pharmacological and genetic ablation approaches. We found that SIRT2 KO (knockout) mice exhibited improved functional recovery after sciatic nerve crush. SIRT2 activity blockage, using AK7, increased neurite outgrowth and length in organotypic spinal cord cultures and human cell line models. SIRT2 blockage enhanced the acetyltransferase activity of p300, which in turn increased the levels of an acetylated form of p53 (Ac-p53 k373), histone 3 (Ac-H3K9), and expression of GAP43, a downstream marker of regeneration. Lastly, we verified that p300 acetyltransferase activity is essential for these effects. Our results suggest that bolstering an epigenetic shift that promotes SIRT2 inhibition can be an effective therapy to increase functional recovery after peripheral nerve injury.

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Section: Discussionmentioning

confidence: 99%

SIRT2 Inhibition Improves Functional Motor Recovery After Peripheral Nerve Injury

Leiva-Rodríguez

Casas

2020

Neurotherapeutics

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“…In reality, axon regeneration is a complex process that is dependent on the degree of injury, the extent of neuron sparing, the types of neuron involved, and various other factors. With regards to the possibility of species differences in axonal regeneration, the process of axonal fusion that occurs spontaneously in some invertebrate species [109] would enhance nerve repair in ways that are perhaps independent of NMNAT and PTEN.…”

Section: Perspectivesmentioning

confidence: 99%

Why is NMNAT Protective against Neuronal Cell Death and Axon Degeneration, but Inhibitory of Axon Regeneration?

Tang

2019

Cells

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Nicotinamide mononucleotide adenylyltransferase (NMNAT), a key enzyme for NAD+ synthesis, is well known for its activity in neuronal survival and attenuation of Wallerian degeneration. Recent investigations in invertebrate models have, however, revealed that NMNAT activity negatively impacts upon axon regeneration. Overexpression of Nmnat in laser-severed Drosophila sensory neurons reduced axon regeneration, while axon regeneration was enhanced in injured mechanosensory axons in C. elegans nmat-2 null mutants. These diametrically opposite effects of NMNAT orthologues on neuroprotection and axon regeneration appear counterintuitive as there are many examples of neuroprotective factors that also promote neurite outgrowth, and enhanced neuronal survival would logically facilitate regeneration. We suggest here that while NMNAT activity and NAD+ production activate neuroprotective mechanisms such as SIRT1-mediated deacetylation, the same mechanisms may also activate a key axonal regeneration inhibitor, namely phosphatase and tensin homolog (PTEN). SIRT1 is known to deacetylate and activate PTEN which could, in turn, suppress PI3 kinase–mTORC1-mediated induction of localized axonal protein translation, an important process that determines successful regeneration. Strategic tuning of Nmnat activity and NAD+ production in axotomized neurons may thus be necessary to promote initial survival without inhibiting subsequent regeneration.

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“…As the size of the spinal cord increases in adulthood, axons regeneration often takes a long time to extend longer distances [ 9 ]. Besides, the surrounding inhibitory environment prevents the regenerating axon from re-connecting with the target tissue [ 10 ]. Therefore, achieving new functional connections and eliminating the inhibition from the surrounding environment have turned out a significant challenge for regenerative medicine [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Application of fibrin-based hydrogels for nerve protection and regeneration after spinal cord injury

Xia

et al. 2020

J Biol Eng

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Traffic accidents, falls, and many other events may cause traumatic spinal cord injuries (SCIs), resulting in nerve cells and extracellular matrix loss in the spinal cord, along with blood loss, inflammation, oxidative stress (OS), and others. The continuous development of neural tissue engineering has attracted increasing attention on the application of fibrin hydrogels in repairing SCIs. Except for excellent biocompatibility, flexibility, and plasticity, fibrin, a component of extracellular matrix (ECM), can be equipped with cells, ECM protein, and various growth factors to promote damage repair. This review will focus on the advantages and disadvantages of fibrin hydrogels from different sources, as well as the various modifications for internal topographical guidance during the polymerization. From the perspective of further improvement of cell function before and after the delivery of stem cell, cytokine, and drug, this review will also evaluate the application of fibrin hydrogels as a carrier to the therapy of nerve repair and regeneration, to mirror the recent development tendency and challenge.

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Axonal fusion: An alternative and efficient mechanism of nerve repair

Cited by 24 publications

References 202 publications

SIRT2 Inhibition Improves Functional Motor Recovery After Peripheral Nerve Injury

SIRT2 Inhibition Improves Functional Motor Recovery After Peripheral Nerve Injury

Why is NMNAT Protective against Neuronal Cell Death and Axon Degeneration, but Inhibitory of Axon Regeneration?

Application of fibrin-based hydrogels for nerve protection and regeneration after spinal cord injury

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