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International Journal of Molecular... Nov 2020Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries... (Review)
Review
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.
Topics: Animals; Axons; Humans; Muscle, Skeletal; Nerve Regeneration; Neurogenesis; Peripheral Nerve Injuries; Peripheral Nerves; Recovery of Function; Schwann Cells; Tacrolimus
PubMed: 33212795
DOI: 10.3390/ijms21228652 -
Cold Spring Harbor Perspectives in... Jun 2015Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin... (Review)
Review
Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons.
Topics: Axons; Glycolysis; Models, Biological; Myelin Sheath; Oligodendroglia; Synaptic Transmission
PubMed: 26101081
DOI: 10.1101/cshperspect.a020479 -
The Journal of Clinical Investigation Sep 2017Spinal cord injury (SCI) lesions present diverse challenges for repair strategies. Anatomically complete injuries require restoration of neural connectivity across... (Review)
Review
Spinal cord injury (SCI) lesions present diverse challenges for repair strategies. Anatomically complete injuries require restoration of neural connectivity across lesions. Anatomically incomplete injuries may benefit from augmentation of spontaneous circuit reorganization. Here, we review SCI cell biology, which varies considerably across three different lesion-related tissue compartments: (a) non-neural lesion core, (b) astrocyte scar border, and (c) surrounding spared but reactive neural tissue. After SCI, axon growth and circuit reorganization are determined by neuron-cell-autonomous mechanisms and by interactions among neurons, glia, and immune and other cells. These interactions are shaped by both the presence and the absence of growth-modulating molecules, which vary markedly in different lesion compartments. The emerging understanding of how SCI cell biology differs across lesion compartments is fundamental to developing rationally targeted repair strategies.
Topics: Animals; Astrocytes; Axons; Cell Proliferation; Inflammation; Mice; Nerve Regeneration; Neuroglia; Neurons; Spinal Cord; Spinal Cord Injuries; Synapses
PubMed: 28737515
DOI: 10.1172/JCI90608 -
Neuron Jan 2023The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion of protein tyrosine...
The coordination mechanism of neural innate immune responses for axon regeneration is not well understood. Here, we showed that neuronal deletion of protein tyrosine phosphatase non-receptor type 2 sustains the IFNγ-STAT1 activity in retinal ganglion cells (RGCs) to promote axon regeneration after injury, independent of mTOR or STAT3. DNA-damage-induced cGAMP synthase (cGAS)-stimulator of interferon genes (STINGs) activation is the functional downstream signaling. Directly activating neuronal STING by cGAMP promotes axon regeneration. In contrast to the central axons, IFNγ is locally translated in the injured peripheral axons and upregulates cGAS expression in Schwann cells and infiltrating blood cells to produce cGAMP, which promotes spontaneous axon regeneration as an immunotransmitter. Our study demonstrates that injured peripheral nervous system (PNS) axons can direct the environmental innate immune response for self-repair and that the neural antiviral mechanism can be harnessed to promote axon regeneration in the central nervous system (CNS).
Topics: Axons; Nerve Regeneration; Retinal Ganglion Cells; Immunity, Innate; Nucleotidyltransferases
PubMed: 36370710
DOI: 10.1016/j.neuron.2022.10.028 -
Neuroscience Research Dec 2023The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD... (Review)
Review
The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD precursor NMN binds to and activates the pro-degenerative enzyme SARM1, so a failure to convert sufficient NMN into NAD leads to toxic NMN accumulation and axon degeneration. This involvement of NMN brings the axon degeneration field to an unexpected overlap with research into ageing and extending healthy lifespan. A decline in NAD levels throughout life, at least in some tissues, is believed to contribute to age-related functional decay and boosting NAD production with supplementation of NMN or other NAD precursors has gained attention as a potential anti-ageing therapy. Recent years have witnessed an influx of NMN-based products and related molecules on the market, sold as food supplements, with many people taking these supplements daily. While several clinical trials are ongoing to check the safety profiles and efficacy of NAD precursors, sufficient data to back their therapeutic use are still lacking. Here, we discuss NMN supplementation, SARM1 and anti-ageing strategies, with an important question in mind: considering that NMN accumulation can lead to axon degeneration, how is this compatible with its beneficial effect in ageing and are there circumstances in which NMN supplementation could become harmful?
Topics: Humans; NAD; Axons; Aging
PubMed: 36657725
DOI: 10.1016/j.neures.2023.01.004 -
Neuron Jan 2022Axons in the adult mammalian central nervous system fail to regenerate after spinal cord injury. Neurons lose their capacity to regenerate during development, but the...
Axons in the adult mammalian central nervous system fail to regenerate after spinal cord injury. Neurons lose their capacity to regenerate during development, but the intracellular processes underlying this loss are unclear. We found that critical components of the presynaptic active zone prevent axon regeneration in adult mice. Transcriptomic analysis combined with live-cell imaging revealed that adult primary sensory neurons downregulate molecular constituents of the synapse as they acquire the ability to rapidly grow their axons. Pharmacogenetic reduction of neuronal excitability stimulated axon regeneration after adult spinal cord injury. Genetic gain- and loss-of-function experiments uncovered that essential synaptic vesicle priming proteins of the presynaptic active zone, but not clostridial-toxin-sensitive VAMP-family SNARE proteins, inhibit axon regeneration. Systemic administration of Baclofen reduced voltage-dependent Ca influx in primary sensory neurons and promoted their regeneration after spinal cord injury. These findings indicate that functional presynaptic active zones constitute a major barrier to axon regeneration.
Topics: Animals; Axons; Central Nervous System; Mammals; Mice; Nerve Regeneration; Neurons; Spinal Cord Injuries
PubMed: 34706221
DOI: 10.1016/j.neuron.2021.10.007 -
Developmental Cell Feb 2022Regeneration of adult mammalian central nervous system (CNS) axons is abortive, resulting in inability to recover function after CNS lesion, including spinal cord injury...
Regeneration of adult mammalian central nervous system (CNS) axons is abortive, resulting in inability to recover function after CNS lesion, including spinal cord injury (SCI). Here, we show that the spiny mouse (Acomys) is an exception to other mammals, being capable of spontaneous and fast restoration of function after severe SCI, re-establishing hind limb coordination. Remarkably, Acomys assembles a scarless pro-regenerative tissue at the injury site, providing a unique structural continuity of the initial spinal cord geometry. The Acomys SCI site shows robust axon regeneration of multiple tracts, synapse formation, and electrophysiological signal propagation. Transcriptomic analysis of the spinal cord following transcriptome reconstruction revealed that Acomys rewires glycosylation biosynthetic pathways, culminating in a specific pro-regenerative proteoglycan signature at SCI site. Our work uncovers that a glycosylation switch is critical for axon regeneration after SCI and identifies β3gnt7, a crucial enzyme of keratan sulfate biosynthesis, as an enhancer of axon growth.
Topics: Animals; Axons; Disease Models, Animal; Glycosylation; Mice; Nerve Regeneration; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Spine
PubMed: 34986324
DOI: 10.1016/j.devcel.2021.12.008 -
The Journal of Neuroscience : the... Nov 2022Axons differ in their growth potential: whereas during development, axons rapidly grow to their targets, in the adult mammalian, CNS axons have lost their ability to...
Axons differ in their growth potential: whereas during development, axons rapidly grow to their targets, in the adult mammalian, CNS axons have lost their ability to grow and therefore fail to regenerate. Recent progress has enabled a better understanding of how developmental mechanisms direct axon regeneration. Focusing on neuronal polarization, where one neurite is singled out to become the axon, has uncovered the mechanisms initiating axon growth and growth restraint. This has helped to define the processes that need to be reactivated to induce axon regeneration: microtubule stabilization and actin dynamics. The molecular machinery underlying axon growth and axon regeneration is remarkably similar and includes the Rho-GTPases Cdc42, Rac-1, and RhoA, as well as the actin regulators cofilin and Myosin II. Importantly, neuron-intrinsic growth inhibitors in the adult nervous system, including the voltage-gated calcium channel subunit α2δ2 and the presynaptic active zone protein Munc13, restrain dynamics while the components driving axon growth remain largely present. The identified molecules suggest that synaptic transmission and axon growth may be processes that exclude each other. As a result, axon regeneration may be hampered by synaptic transmission and, thus, by the maturation of the CNS. This research has led to several translational avenues to induce axon regeneration and functional recovery after spinal cord injury and stroke; these include the drugs epothilones, gabapentinoids, and baclofen. Thus, the investigation of axon growth and regeneration side by side has been instrumental to coax the regenerative potential of the CNS.
Topics: Animals; Humans; Axons; Nerve Regeneration; Actins; Neurons; Spinal Cord Injuries; Mammals
PubMed: 36351827
DOI: 10.1523/JNEUROSCI.1131-22.2022 -
International Journal of Molecular... Jul 2020The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While... (Review)
Review
The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon-environment and axon-target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon-axon interactions during the different steps of neural circuit formation.
Topics: Animals; Axons; Fasciculation; Growth Cones; Neural Conduction; Signal Transduction
PubMed: 32708320
DOI: 10.3390/ijms21145170 -
Molecular & Cellular Proteomics : MCP Feb 2016Neurons are extremely polarized cells. Axon lengths often exceed the dimension of the neuronal cell body by several orders of magnitude. These extreme axonal lengths... (Review)
Review
Neurons are extremely polarized cells. Axon lengths often exceed the dimension of the neuronal cell body by several orders of magnitude. These extreme axonal lengths imply that neurons have mastered efficient mechanisms for long distance signaling between soma and synaptic terminal. These elaborate mechanisms are required for neuronal development and maintenance of the nervous system. Neurons can fine-tune long distance signaling through calcium wave propagation and bidirectional transport of proteins, vesicles, and mRNAs along microtubules. The signal transmission over extreme lengths also ensures that information about axon injury is communicated to the soma and allows for repair mechanisms to be engaged. This review focuses on the different mechanisms employed by neurons to signal over long axonal distances and how signals are interpreted in the soma, with an emphasis on proteomic studies. We also discuss how proteomic approaches could help further deciphering the signaling mechanisms operating over long distance in axons.
Topics: Axons; Calcium Signaling; Cell Polarity; Humans; Nervous System; Neurons; Proteomics; Synaptic Transmission
PubMed: 26297514
DOI: 10.1074/mcp.R115.052753