Injury-Induced Decline of Intrinsic Regenerative Ability Revealed by Quantitative Proteomics

Belin, Stéphane; Nawabi, Homaira; Wang, Chen; Tang, Shao-Jun; Latrémolière, Alban; Warren, Peter; Schorle, Hubert; Uncu, Ceren; Woolf, Clifford J.; He, Zhigang; Steen, Judith A.

doi:10.1016/j.neuron.2015.03.060

Cited by 206 publications

(220 citation statements)

References 59 publications

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“…Although AAV-hIL-6 was applied right after optic nerve lesion instead of prior to injury as described for previous experimental manipulations, the regenerative response was even comparable to levels achieved upon PTEN deletion in combination with CNTF application/IS. 6,23,41,44,45 Conceivably, it might be possible to further increase the number and length of regenerating axons by applying AAV-hIL-6 prior to injury or by using combinations with other previously reported genetic approaches, 23,35,41,[46][47][48][49][50] as demonstrated by the combination of hIL-6 expression with RGC-specific PTEN knockout.…”

Section: Discussionmentioning

confidence: 99%

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

et al. 2016

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Retinal ganglion cells (RGCs) do not normally regenerate injured axons, but die upon axotomy. Although IL-6-like cytokines are reportedly neuroprotective and promote optic nerve regeneration, their overall regenerative effects remain rather moderate. Here, we hypothesized that direct activation of the gp130 receptor by the designer cytokine hyper-IL-6 (hIL-6) might induce stronger RGC regeneration than natural cytokines. Indeed, hIL-6 stimulated neurite growth of adult cultured RGCs with significantly higher efficacy than CNTF or IL-6. This neurite growth promoting effect could be attributed to stronger activation of the JAK/STAT3 and PI3K/AKT/mTOR signaling pathways and was also observed in peripheral dorsal root ganglion neurons. Moreover, hIL-6 abrogated axon growth inhibition by central nervous system (CNS) myelin. Remarkably, continuous hIL-6 expression upon RGC-specific AAV transduction after optic nerve crush exerted stronger axon regeneration than other known regeneration promoting treatments such as lens injury and PTEN knockout, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Combination of hIL-6 with RGC-specific PTEN knockout further enhanced optic nerve regeneration. Therefore, direct activation of gp130 signaling might be a novel, clinically applicable approach for robust CNS repair.

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Section: Discussionmentioning

confidence: 99%

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

et al. 2016

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“…These proteins could be functionally classified into signal transduction, guanosine triphosphate activity, microtubule-based transport, and metabolism (47). Most recently, Steen and colleagues used a tandem mass tag (TMT) proteomics approach to uncover c-myc as a central injury-response hub in retinal ganglion cells (51). Quantitative mass spectrometry revealed several pathways altered after retinal ganglion injury including p53, MAPK, NF-B, and Huntington protein.…”

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confidence: 99%

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

Niekerk

Tuszynski

et al. 2016

Molecular & Cellular Proteomics

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Following axotomy, a complex temporal and spatial coordination of molecular events enables regeneration of the peripheral nerve. In contrast, multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration in the central nervous system. In this review, we examine the current understanding of differences in protein expression and post-translational modifications, activation of signaling networks, and environmental cues that may underlie the divergent regenerative capacity of central and peripheral axons. We also highlight key experimental strategies to enhance axonal regeneration via modulation of intraneuronal signaling networks and the extracellular milieu. Finally, we explore potential applications of proteomics to fill gaps in the current understanding of molecular mechanisms underlying regeneration, and to provide insight into the development of more effective approaches to promote axonal regeneration following injury to the nervous system. Molecular & Cellular Proteomics

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“…Importantly, surgical parameters, such as the duration of the crush or the distance of the crush site from the eye, can vary among research groups, which may contribute to differences in the timing and progress of the molecular and cellular processes following ONC. During the last decade, it has repeatedly been shown that RGCs can be induced to regrow axons over long distances after optic nerve injury (Sun et al 2011;Pernet et al 2013b;Belin et al 2015;Bohm et al 2015;Duan et al 2015;Li et al 2015;Sharma et al 2015). Treatments that stimulate the acute inflammatory response after ONC, such as lens injury or intravitreal injection of either the yeast cell-wall extract zymosan or the lipopeptide Pam3Cys, have proven to promote axon growth (Fischer and Leibinger 2012;Benowitz et al 2017).…”

Section: Models and Methods To Induce Optic Nerve Regenerationmentioning

confidence: 99%

Complementary research models and methods to study axonal regeneration in the vertebrate retinofugal system

et al. 2017

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Due to the lack of axonal regeneration, age-related deterioration in the central nervous system (CNS) poses a significant burden on the wellbeing of a growing number of elderly. To overcome this regenerative failure and to improve the patient's life quality, the search for novel regenerative treatment strategies requires valuable (animal) models and techniques. As an extension of the CNS, the retinofugal system, consisting of retinal ganglion cells that send their axons along the optic nerve to the visual brain areas, has importantly contributed to the current knowledge on mechanisms underlying the restricted regenerative capacities and to the development of novel strategies to enhance axonal regeneration. It provides an extensively used research tool, not only in amniote vertebrates including rodents, but also in anamniote vertebrates, such as zebrafish. Indeed, the latter show robust regeneration capacities, thereby providing insights into the factors that contribute to axonal regrowth and proper guidance, complementing studies in mammals. This review provides an integrative and critical overview of the classical and state-of-the-art models and methods that have been employed in the retinofugal system to advance our knowledge on the signaling pathways underlying the restricted versus robust axonal regeneration in rodents and zebrafish, respectively. In vitro, ex vivo and in vivo models and techniques to improve the visualization and analysis of regenerating axons are summarized. As such, the retinofugal system is presented as a valuable model to further facilitate research on axonal regeneration and to open novel therapeutic avenues for CNS pathologies.

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Injury-Induced Decline of Intrinsic Regenerative Ability Revealed by Quantitative Proteomics

Cited by 206 publications

References 59 publications

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

Complementary research models and methods to study axonal regeneration in the vertebrate retinofugal system

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