Translating regeneration: Local protein synthesis in the neuronal injury response

Koley, Sandip; Rozenbaum, Meir; Fainzilber, Mike; Terenzio, Marco

doi:10.1016/j.neures.2018.10.003

Cited by 31 publications

(26 citation statements)

References 174 publications

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“…This would explain the downregulation observed from T3 to T14 and the subsequent upregulation at T21, when axons regenerate. Whether L-Pgds mRNA is locally translated in injured axons as it occurs for other proteins is not known (Koley, Rozenbaum, Fainzilber, & Terenzio, 2019;Spaulding & Burgess, 2017;Terenzio et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

Forese

Pellegatta

Canevazzi

et al. 2019

Glia

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We have previously reported that prostaglandin D2 Synthase (L‐PGDS) participates in peripheral nervous system (PNS) myelination during development. We now describe the role of L‐PGDS in the resolution of PNS injury, similarly to other members of the prostaglandin synthase family, which are important for Wallerian degeneration (WD) and axonal regeneration. Our analyses show that L‐PGDS expression is modulated after injury in both sciatic nerves and dorsal root ganglia neurons, indicating that it might play a role in the WD process. Accordingly, our data reveals that L‐PGDS regulates macrophages phagocytic activity through a non‐cell autonomous mechanism, allowing myelin debris clearance and favoring axonal regeneration and remyelination. In addition, L‐PGDS also appear to control macrophages accumulation in injured nerves, possibly by regulating the blood–nerve barrier permeability and SOX2 expression levels in Schwann cells. Collectively, our results suggest that L‐PGDS has multiple functions during nerve regeneration and remyelination. Based on the results of this study, we posit that L‐PGDS acts as an anti‐inflammatory agent in the late phases of WD, and cooperates in the resolution of the inflammatory response. Thus, pharmacological activation of the L‐PGDS pathway might prove beneficial in resolving peripheral nerve injury.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

Forese

Pellegatta

Canevazzi

et al. 2019

Glia

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“…After nerve injuries that isolate the distal stump from the neuronal soma, the proximal nerve stump degenerates to the first node of Ranvier prior to sealing the membrane within hours [17,[73][74][75][76].…”

Section: Neuronal and Schwann Cell Responses To Injurymentioning

confidence: 99%

“…The mTOR mRNA from the cell body binds to nucleolin for anterograde transport by the kinesin motor to the injury site. There it is translated locally [75]. In the axon, the mTOR protein controls its own mRNA translation and that of many localized mRNAs.…”

Section: Neuronal and Schwann Cell Responses To Injurymentioning

confidence: 99%

“…In the axon, the mTOR protein controls its own mRNA translation and that of many localized mRNAs. These include the transcription factors that bind to dynein via adaptor proteins such as importin β1, to transport them retrogradely to the neuronal nucleus where they, in turn, regulate transcriptional responses [75,80].…”

Section: Neuronal and Schwann Cell Responses To Injurymentioning

confidence: 99%

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Peripheral Nerve Regeneration and Muscle Reinnervation

Gordon

2020

IJMS

209

144

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Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.

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“…Axon regeneration upon injury is much more difficult in CNS neurons compared to peripheral neurons and is influenced by both external inhibitory factors within the injury environment [16], as well as by neuronal intrinsic factors and mechanisms [17,18]. Important intrinsic processes that facilitate axon regeneration include proper axonal mRNA localization, as well as adequate injury-induced local protein synthesis [19,20] and turnover [21]. In this regard, the mechanistic target of rapamycin (mTOR) [22] functions as a master regulator whose activation enhances mRNA translation and protein synthesis at the soma, as well as locally in the axon [23].…”

Section: Introductionmentioning

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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Translating regeneration: Local protein synthesis in the neuronal injury response

Cited by 31 publications

References 174 publications

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

Prostaglandin D2 synthase modulates macrophage activity and accumulation in injured peripheral nerves

Peripheral Nerve Regeneration and Muscle Reinnervation

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

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