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Mark H Tuszynski - One of the best experts on this subject based on the ideXlab platform.
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Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury
Molecular & Cellular Proteomics, 2015Co-Authors: Erna A. Van Niekerk, Mark H Tuszynski, Jennifer N. DulinAbstract: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.
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snon facilitates Axonal Regeneration after spinal cord injury
PLOS ONE, 2013Co-Authors: Azad Bonni, Mark H TuszynskiAbstract:Adult CNS neurons exhibit a reduced capacity for growth compared to developing neurons, due in part to downregulation of growth-associated genes as development is completed. We tested the hypothesis that SnoN, an embryonically regulated transcription factor that specifies growth of the Axonal compartment, can enhance growth in injured adult neurons. In vitro, SnoN overexpression in dissociated adult DRG neuronal cultures significantly enhanced neurite outgrowth. Moreover, TGF-β1, a negative regulator of SnoN, inhibited neurite outgrowth, and SnoN over-expression overcame this inhibition. We then examined whether SnoN influenced Axonal Regeneration in vivo: indeed, expression of a mutant form of SnoN resistant to degradation significantly enhanced Axonal Regeneration following cervical spinal cord injury, despite peri-lesional upregulation of TGF-β1. Thus, a developmental mechanism that specifies extension of the Axonal compartment also promotes Axonal Regeneration after adult CNS injury.
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conditioning lesions before or after spinal cord injury recruit broad genetic mechanisms that sustain Axonal Regeneration superiority to camp mediated effects
Experimental Neurology, 2012Co-Authors: Armin Blesch, Shingo Tsukada, Laura Taylor Alto, Kasper C D Roet, Giovanni Coppola, Daniel H Geschwind, Mark H TuszynskiAbstract:Previous studies indicate that peripheral nerve conditioning lesions significantly enhance central Axonal Regeneration via modulation of cAMP-mediated mechanisms. To gain insight into the nature and temporal dependence of neural mechanisms underlying conditioning lesion effects on central Axonal Regeneration, we compared the efficacy of peripheral sciatic nerve crush lesions to cAMP elevations (in lumbar dorsal root ganglia) on central sensory Axonal Regeneration when administered either before or after cervical spinal cord lesions. We found significantly greater effects of conditioning lesions compared to cAMP elevations on central Axonal Regeneration when combined with cellular grafts at the lesion site and viral neurotrophin delivery; further, these effects persisted whether conditioning lesions were applied prior to or shortly after spinal cord injury. Indeed, conditioning lesions recruited extensively greater sets of genetic mechanisms of possible relevance to Axonal Regeneration compared to cAMP administration, and sustained these changes for significantly greater time periods through the post-lesion period. We conclude that cAMP-mediated mechanisms account for only a portion of the potency of conditioning lesions on central Axonal Regeneration, and that recruitment of broader genetic mechanisms can extend the effect and duration of cellular events that support Axonal growth.
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Templated agarose scaffolds support linear Axonal Regeneration.
Tissue Engineering, 2006Co-Authors: Shula Stokols, Jeff Sakamoto, Chris Breckon, Todd E. Holt, James R. Weiss, Mark H TuszynskiAbstract:While several strategies can stimulate Axonal Regeneration within a site of spinal cord injury, the growth of axons is generally disorganized and random. Biocompatible scaffolds that guide and main...
Stephen M. Strittmatter - One of the best experts on this subject based on the ideXlab platform.
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functional genome wide screen identifies pathways restricting central nervous system Axonal Regeneration
Cell Reports, 2018Co-Authors: Yuichi Sekine, Zhaoxin Jiang, Alexander T Linmoore, Devon M Chenette, Xingxing Wang, William B J Cafferty, Marc Hammarlund, Stephen M. StrittmatterAbstract:Summary Axonal regrowth is crucial for recovery from CNS injury but is severely restricted in adult mammals. We used a genome-wide loss-of-function screen for factors limiting Axonal Regeneration from cerebral cortical neurons in vitro . Knockdown of 16,007 individual genes identified 580 significant phenotypes. These molecules share no significant overlap with those suggested by previous expression profiles. There is enrichment for genes in pathways related to transport, receptor binding, and cytokine signaling, including Socs4 and Ship2. Among transport-regulating proteins, Rab GTPases are prominent. In vivo assessment with C. elegans validates a cell-autonomous restriction of Regeneration by Rab27. Mice lacking Rab27b show enhanced retinal ganglion cell axon Regeneration after optic nerve crush and greater motor function and raphespinal sprouting after spinal cord trauma. Thus, a comprehensive functional screen reveals multiple pathways restricting Axonal Regeneration and neurological recovery after injury.
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Regulation of Axonal Regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS
Scientific Reports, 2017Co-Authors: Tomoko Hirokawa, Stephen M. Strittmatter, Yuji Kurihara, Zhaoxin Jiang, Yusuke Sakakibara, Kengo Funakoshi, Nobutaka Kawahara, Yoshio Goshima, Kohtaro TakeiAbstract:Axonal Regeneration in the adult mammalian central nervous system is limited in part by the non-permissive environment, including Axonal growth inhibitors such as the Nogo-A protein. How the functions of these inhibitors can be blocked remains unclear. Here, we examined the role of LOTUS, an endogenous Nogo receptor antagonist, in promoting functional recovery and neural repair after spinal cord injury (SCI), as well as Axonal Regeneration after optic nerve crush. Wild-type untreated mice show incomplete but substantial intrinsic motor recovery after SCI. The genetic deletion of LOTUS delays and decreases the extent of motor recovery, suggesting that LOTUS is required for spontaneous neural repair. The neuronal overexpression of LOTUS in transgenic mice promotes motor recovery after SCI, and recombinant viral overexpression of LOTUS enhances retinal ganglion cell Axonal Regeneration after optic nerve crush. Thus, the level of LOTUS function titrates Axonal Regeneration.
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nogo 66 receptor antagonist peptide promotes Axonal Regeneration
Nature, 2002Co-Authors: Tadzia Grandpre, Shuxin Li, Stephen M. StrittmatterAbstract:Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of Axonal Regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes1 and can inhibit Axonal outgrowth through an Axonal Nogo-66 receptor (NgR)2. The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract Regeneration and locomotor recovery3,4,5; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1–40) antagonist peptide (NEP1–40) blocks Nogo-66 or CNS myelin inhibition of Axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of Axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1–40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting Axonal Regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.
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nogo 66 receptor antagonist peptide promotes Axonal Regeneration
Nature, 2002Co-Authors: Tadzia Grandpre, Stephen M. StrittmatterAbstract:Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of Axonal Regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes1 and can inhibit Axonal outgrowth through an Axonal Nogo-66 receptor (NgR)2. The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract Regeneration and locomotor recovery3,4,5; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1–40) antagonist peptide (NEP1–40) blocks Nogo-66 or CNS myelin inhibition of Axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of Axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1–40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting Axonal Regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.
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Modulation of Axonal Regeneration in neurodegenerative disease: focus on Nogo.
Journal of Molecular Neuroscience, 2002Co-Authors: Stephen M. StrittmatterAbstract:Recent work has demonstrated that Axonal Regeneration in the central nervous system is limited by myelin-derived Nogo binding to an Axonal Nogo Receptor. The Nogo system appears to have a physiologic role in regulating structural plasticity. The possibility that the Nogo system contributes to pathologic and compensatory plasticity in Alzheimer's Disease is considered.
Andrew W Boyd - One of the best experts on this subject based on the ideXlab platform.
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epha4 blockers promote Axonal Regeneration and functional recovery following spinal cord injury in mice
PLOS ONE, 2011Co-Authors: Yona Goldshmit, Mark D Spanevello, Sophie Tajouri, F Rogers, Martin J Pearse, Mary P Galea, Perry F Bartlett, Andrew W BoydAbstract:Upregulation and activation of developmental axon guidance molecules, such as semaphorins and members of the Eph receptor tyrosine kinase family and their ligands, the ephrins, play a role in the inhibition of Axonal Regeneration following injury to the central nervous system. Previously we have demonstrated in a knockout model that Axonal Regeneration following spinal cord injury is promoted in the absence of the axon guidance protein EphA4. Antagonism of EphA4 was therefore proposed as a potential therapy to promote recovery from spinal cord injury. To further assess this potential, two soluble recombinant blockers of EphA4, unclustered ephrin-A5-Fc and EphA4-Fc, were examined for their ability to promote Axonal Regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial Axonal Regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocytic gliosis, indicating that much of the effect of the blockers may be due to promotion of axon growth. These studies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for the treatment of other central nervous system injuries.
Inge Van Hove - One of the best experts on this subject based on the ideXlab platform.
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Complementary research models and methods to study Axonal Regeneration in the vertebrate retinofugal system
Brain Structure and Function, 2017Co-Authors: Ilse Bollaerts, Lien Veys, Emiel Geeraerts, Tom Buyens, Lies De Groef, Manuel Salinas-navarro, Lien Andries, Lieve Moons, Inge Van HoveAbstract: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.
Sang Ryong Jeon - One of the best experts on this subject based on the ideXlab platform.
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Axonal Regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats
Acta Neurochirurgica, 2011Co-Authors: Hyung Il Suh, Joongkee Min, Kyung Hyo Choi, Seong Who Kim, Ki Soo Kim, Sang Ryong JeonAbstract:Background Axonal Regeneration is a prerequisite for recovery from spinal cord injury. Here, we investigated whether Wnt3a-secreting fibroblasts exert a favorable effect on spinal cord Regeneration in spinal cord-injured rats. Methods Spinal cord injury (SCI) was induced in rats ( n = 21) using an NYU impactor. One week after SCI, rats were assigned to a Wnt3a-secreting fibroblast transplantation group (Wnt group, n = 7), a L929 fibroblast transplantation group (vehicle group, n = 7), and contusion only group (sham group, n = 7). Motor function was tested weekly for 6 weeks. Manganese-enhanced magnetic resonance imaging (ME-MRI) was performed twice, once before cell transplantation and again 5 weeks after cell transplantation. After ME-MRI, expression of the Axonal Regeneration marker GAP-43 was assessed by immunohistochemistry (IHC). Results In the Wnt group, the mean Basso–Beattie–Bresnahan score was higher than that of the vehicle and sham groups throughout the observation period. The Wnt group also exhibited stronger signal intensity on ME-MRI, and IHC revealed that GAP-43 was highly expressed in the injured spinal cord in the Wnt group. Conclusions These results strongly suggest that transplanted Wnt3a secreting fibroblasts promote Axonal Regeneration and functional improvement after SCI. Although further investigation will be necessary to clarify the intracellular mechanism by which Wnt signaling promotes Axonal Regeneration and functional improvement, this approach could be a highly promising therapeutic strategy for SCI.
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Axonal Regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats
Acta Neurochirurgica, 2011Co-Authors: Hyung Il Suh, Joongkee Min, Kyung Hyo Choi, Seong Who Kim, Ki Soo Kim, Sang Ryong JeonAbstract:Background Axonal Regeneration is a prerequisite for recovery from spinal cord injury. Here, we investigated whether Wnt3a-secreting fibroblasts exert a favorable effect on spinal cord Regeneration in spinal cord-injured rats.