scholarly journals Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

2021 ◽  
Vol 22 (4) ◽  
pp. 1798
Author(s):  
Veselina Petrova ◽  
Bart Nieuwenhuis ◽  
James W. Fawcett ◽  
Richard Eva
Keyword(s):  
Molecular Mechanisms ◽  
Vision Loss ◽  
Axon Regeneration ◽  
Recent Literature ◽  
Axon Growth ◽  
Recycling Endosomes ◽  
Axon Extension ◽  
Cord Injury ◽  
Cone Development ◽  
New Strategies

Investigating the molecular mechanisms governing developmental axon growth has been a useful approach for identifying new strategies for boosting axon regeneration after injury, with the goal of treating debilitating conditions such as spinal cord injury and vision loss. The picture emerging is that various axonal organelles are important centers for organizing the molecular mechanisms and machinery required for growth cone development and axon extension, and these have recently been targeted to stimulate robust regeneration in the injured adult central nervous system (CNS). This review summarizes recent literature highlighting a central role for organelles such as recycling endosomes, the endoplasmic reticulum, mitochondria, lysosomes, autophagosomes and the proteasome in developmental axon growth, and describes how these organelles can be targeted to promote axon regeneration after injury to the adult CNS. This review also examines the connections between these organelles in developing and regenerating axons, and finally discusses the molecular mechanisms within the axon that are required for successful axon growth.

scholarly journals The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1078
Author(s):  
Debasish Roy ◽  
Andrea Tedeschi
Keyword(s):  
Nervous System ◽  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Axon Regeneration ◽  
Axon Growth ◽  
The Body ◽  
Cns Repair ◽  
Cord Injury ◽  
Cns Trauma

Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.

scholarly journals Chondroitinase ABC Promotes Axon Regeneration and Reduces Retrograde Apoptosis Signaling in Lamprey

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianli Hu ◽  
William Rodemer ◽  
Guixin Zhang ◽  
Li-Qing Jin ◽  
Shuxin Li ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Axonal Regeneration ◽  
Neuronal Apoptosis ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Chondroitinase Abc ◽  
Apoptotic Signaling ◽  
Akt Activation ◽  
Collateral Sprouting ◽  
Cord Injury

Paralysis following spinal cord injury (SCI) is due to failure of axonal regeneration. It is believed that axon growth is inhibited by the presence of several types of inhibitory molecules in central nervous system (CNS), including the chondroitin sulfate proteoglycans (CSPGs). Many studies have shown that digestion of CSPGs with chondroitinase ABC (ChABC) can enhance axon growth and functional recovery after SCI. However, due to the complexity of the mammalian CNS, it is still unclear whether this involves true regeneration or only collateral sprouting by uninjured axons, whether it affects the expression of CSPG receptors such as protein tyrosine phosphatase sigma (PTPσ), and whether it influences retrograde neuronal apoptosis after SCI. In the present study, we assessed the roles of CSPGs in the regeneration of spinal-projecting axons from brainstem neurons, and in the process of retrograde neuronal apoptosis. Using the fluorochrome-labeled inhibitor of caspase activity (FLICA) method, apoptotic signaling was seen primarily in those large, individually identified reticulospinal (RS) neurons that are known to be “bad-regenerators.” Compared to uninjured controls, the number of all RS neurons showing polycaspase activity increased significantly at 2, 4, 8, and 11 weeks post-transection (post-TX). ChABC application to a fresh TX site reduced the number of polycaspase-positive RS neurons at 2 and 11 weeks post-TX, and also reduced the number of active caspase 3-positive RS neurons at 4 weeks post-TX, which confirmed the beneficial role of ChABC treatment in retrograde apoptotic signaling. ChABC treatment also greatly promoted axonal regeneration at 10 weeks post-TX. Correspondingly, PTPσ mRNA expression was reduced in the perikaryon. Previously, PTPσ mRNA expression was shown to correlate with neuronal apoptotic signaling at 2 and 10 weeks post-TX. In the present study, this correlation persisted after ChABC treatment, which suggests that PTPσ may be involved more generally in signaling axotomy-induced retrograde neuronal apoptosis. Moreover, ChABC treatment caused Akt activation (pAkt-308) to be greatly enhanced in brain post-TX, which was further confirmed in individually identified RS neurons. Thus, CSPG digestion not only enhances axon regeneration after SCI, but also inhibits retrograde RS neuronal apoptosis signaling, possibly by reducing PTPσ expression and enhancing Akt activation.

scholarly journals Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wolfgang Pita-Thomas ◽  
Tassia Mangetti Gonçalves ◽  
Ajeet Kumar ◽  
Guoyan Zhao ◽  
Valeria Cavalli
Keyword(s):  
Optic Nerve ◽  
Vision Loss ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Binding Motif ◽  
Open Chromatin ◽  
Transactivation Domain ◽  
Growth Capacity

AbstractRetinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote regeneration of RGC axons, we identified transcription factors (TF) and open chromatin regions that are enriched in rat embryonic RGCs (high axon growth capacity) compared to postnatal RGCs (low axon growth capacity). We found that developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon regeneration. Consistently, overexpression of CREB fused to the VP64 transactivation domain in mouse RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC.

scholarly journals The Application of Omics Technologies to Study Axon Regeneration and CNS Repair

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 311 ◽  
Author(s):  
Andrea Tedeschi ◽  
Phillip G Popovich
Keyword(s):  
Spinal Cord ◽  
Molecular Mechanisms ◽  
Spinal Cord Injuries ◽  
New Technologies ◽  
Axon Regeneration ◽  
Imaging Techniques ◽  
Permanent Disability ◽  
Cord Injury ◽  
Technical Advances ◽  
And Function

Traumatic brain and spinal cord injuries cause permanent disability. Although progress has been made in understanding the cellular and molecular mechanisms underlying the pathophysiological changes that affect both structure and function after injury to the brain or spinal cord, there are currently no cures for either condition. This may change with the development and application of multi-layer omics, new sophisticated bioinformatics tools, and cutting-edge imaging techniques. Already, these technical advances, when combined, are revealing an unprecedented number of novel cellular and molecular targets that could be manipulated alone or in combination to repair the injured central nervous system with precision. In this review, we highlight recent advances in applying these new technologies to the study of axon regeneration and rebuilding of injured neural circuitry. We then discuss the challenges ahead to translate results produced by these technologies into clinical application to help improve the lives of individuals who have a brain or spinal cord injury.

scholarly journals Neuroprotective and Neurorestorative Processes after Spinal Cord Injury: The Case of the Bulbospinal Respiratory Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-15
Author(s):  
Anne Kastner ◽  
Valéry Matarazzo
Keyword(s):  
Spinal Cord ◽  
Molecular Mechanisms ◽  
Spinal Cord Injuries ◽  
Cervical Spinal Cord ◽  
Axon Growth ◽  
Respiratory Neurons ◽  
Partial Recovery ◽  
Respiratory Drive ◽  
Phrenic Motoneurons ◽  
Cord Injury

High cervical spinal cord injuries interrupt the bulbospinal respiratory pathways projecting to the cervical phrenic motoneurons resulting in important respiratory defects. In the case of a lateralized injury that maintains the respiratory drive on the opposite side, a partial recovery of the ipsilateral respiratory function occurs spontaneously over time, as observed in animal models. The rodent respiratory system is therefore a relevant model to investigate the neuroplastic and neuroprotective mechanisms that will trigger such phrenic motoneurons reactivation by supraspinal pathways. Since part of this recovery is dependent on the damaged side of the spinal cord, the present review highlights our current understanding of the anatomical neuroplasticity processes that are developed by the surviving damaged bulbospinal neurons, notably axonal sprouting and rerouting. Such anatomical neuroplasticity relies also on coordinated molecular mechanisms at the level of the axotomized bulbospinal neurons that will promote both neuroprotection and axon growth.

scholarly journals Regeneration of Corticospinal Axons into Neural Progenitor Cell Grafts After Spinal Cord Injury

2020 ◽  
Vol 15 ◽  
pp. 263310552097400
Author(s):  
Gunnar HD Poplawski ◽  
Mark H Tuszynski
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Spinal Cord Injuries ◽  
Axon Regeneration ◽  
Stem Cell Differentiation ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Cord Injury

Spinal cord injuries leave patients with lifelong paralysis. To date, there are no therapies that promote the critical step required for the recovery of voluntary motor function: corticospinal axon regeneration. Spinal cord-derived neural progenitor cell (NPC) grafts integrate into the injured host spinal cord, enable robust corticospinal axon regeneration, and restore forelimb function following spinal cord injury in rodents. Consequently, engineered stem cell differentiation and transplantation techniques harbor promising potential for the design and implementation of therapies promoting corticospinal axon regeneration. However, in order to optimize the outcome of clinical trials, it is critical to fully understand the cellular and molecular mechanisms underlying this regeneration. Our recent study highlights the unexpected intrinsic potential of corticospinal neurons to regenerate and allows us to investigate new hypotheses exploiting this newly discovered potential.

scholarly journals Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration

2021 ◽  
Author(s):  
Wolfgang Pita-Thomas ◽  
Tassia Mangetti Gonçalves ◽  
Guoyan Zhao ◽  
Valeria Cavalli
Keyword(s):  
Optic Nerve ◽  
Vision Loss ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Binding Motif ◽  
Open Chromatin ◽  
Transactivation Domain ◽  
Growth Capacity

Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote RGC axon regeneration, we identified transcription factors (TF) and chromatin accessible sites enriched in embryonic RGCs (high axon growth capacity) compared to postnatal RGC (low axon growth capacity). Developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the differentially opened regions of the chromatin in embryonic RGCs and proteomic analysis confirmed their expression in RGC nuclei. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon growth. Consistently, overexpression of CREB fused to the VP64 transactivation domain in RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC.

scholarly journals Updates and challenges of axon regeneration in the mammalian central nervous system

2020 ◽  
Author(s):  
Cheng Qian ◽  
Feng-Quan Zhou
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Research Progress ◽  
Regeneration Ability ◽  
Long Distance ◽  
Mammalian Central Nervous System ◽  
Cord Injury

Abstract Axon regeneration in the mammalian central nervous system (CNS) has been a long-standing and highly challenging issue. Successful CNS axon regeneration will benefit many human diseases involving axonal damage, such as spinal cord injury, traumatic brain injury, glaucoma, and neurodegenerative diseases. The current consensus is that the diminished intrinsic regenerative ability in mature CNS neurons and the presence of extrinsic inhibitors blocking axon regrowth are two major barriers for axon regeneration. During the past decade, studies targeting the intrinsic axon growth ability via regulation of gene transcription have produced very promising results in optic nerve and/or spinal cord regeneration. Manipulations of various signaling pathways or the nuclear transcription factors directly have been shown to sufficiently drive CNS axon regrowth. Converging evidence reveals that some pro-regenerative transcriptomic states, which are commonly accomplished by more comprehensive epigenetic regulations, exist to orchestrate the complex tasks of injury sensing and axon regeneration. Moreover, genetic reprogramming achieved via transcriptome and epigenome modifications provides novel mechanisms for enhancing axon regeneration. Recent studies also highlighted the important roles of remodeling neuronal cytoskeleton in overcoming the extrinsic inhibitory cues. However, our knowledge about the cellular and molecular mechanisms by which neurons regulate their intrinsic axon regeneration ability and response to extrinsic inhibitory cues is still fragmented. Here, we provide an update about recent research progress in axon regeneration and discuss major remaining challenges for long-distance axon regeneration and the subsequent functional recovery.

scholarly journals Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration

2015 ◽  
Vol 112 (49) ◽  
pp. 15220-15225 ◽  
Author(s):  
Camille Brochier ◽  
James I. Jones ◽  
Dianna E. Willis ◽  
Brett Langley
Keyword(s):  
Molecular Mechanisms ◽  
Axon Regeneration ◽  
Neuronal Loss ◽  
Axon Growth ◽  
Axonal Growth ◽  
Growth Inhibitory ◽  
Physical Barriers ◽  
The Central Nervous System ◽  
Novel Target ◽  
Inhibitory Molecules

Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules—such as myelin-derived Nogo and myelin-associated glycoprotein—or reactive astrocyte-produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration.

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