scholarly journals Ligand-Induced GPR110 Activation Facilitates Axon Growth after Injury

2021 ◽  
Vol 22 (7) ◽  
pp. 3386
Author(s):  
Heungsun Kwon ◽  
Karl Kevala ◽  
Hu Xin ◽  
Samarjit Patnaik ◽  
Juan Marugan ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Neurite Outgrowth ◽  
Nerve Injury ◽  
Cortical Neurons ◽  
Axon Growth ◽  
Neurite Growth ◽  
Nerve Crush ◽  
Developing Neurons

Recovery from axonal injury is extremely difficult, especially for adult neurons. Here, we demonstrate that the activation of G-protein coupled receptor 110 (GPR110, ADGRF1) is a mechanism to stimulate axon growth after injury. N-docosahexaenoylethanolamine (synaptamide), an endogenous ligand of GPR110 that promotes neurite outgrowth and synaptogenesis in developing neurons, and a synthetic GPR110 ligand stimulated neurite growth in axotomized cortical neurons and in retinal explant cultures. Intravitreal injection of GPR110 ligands following optic nerve crush injury promoted axon extension in adult wild-type, but not in gpr110 knockout, mice. In vitro axotomy or in vivo optic nerve injury rapidly induced the neuronal expression of gpr110. Activating the developmental mechanism of neurite outgrowth by specifically targeting GPR110 that is upregulated upon injury may provide a novel strategy for stimulating axon growth after nerve injury in adults.

scholarly journals Citrus Naringenin Increases Neuron Survival in Optic Nerve Crush Injury Model by Inhibiting JNK-JUN Pathway

2021 ◽  
Vol 23 (1) ◽  
pp. 385
Author(s):  
Jie Chen ◽  
Hui Li ◽  
Changming Yang ◽  
Yinjia He ◽  
Tatsuo Arai ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Nerve Injury ◽  
Ganglion Cells ◽  
Crush Injury ◽  
Optic Nerve Crush ◽  
Nerve Crush ◽  
Injury Model ◽  
Nerve Crush Injury

Traumatic nerve injury activates cell stress pathways, resulting in neuronal death and loss of vital neural functions. To date, there are no available neuroprotectants for the treatment of traumatic neural injuries. Here, we studied three important flavanones of citrus components, in vitro and in vivo, to reveal their roles in inhibiting the JNK (c-Jun N-terminal kinase)-JUN pathway and their neuroprotective effects in the optic nerve crush injury model, a kind of traumatic nerve injury in the central nervous system. Results showed that both neural injury in vivo and cell stress in vitro activated the JNK-JUN pathway and increased JUN phosphorylation. We also demonstrated that naringenin treatment completely inhibited stress-induced JUN phosphorylation in cultured cells, whereas nobiletin and hesperidin only partially inhibited JUN phosphorylation. Neuroprotection studies in optic nerve crush injury mouse models revealed that naringenin treatment increased the survival of retinal ganglion cells after traumatic optic nerve injury, while the other two components had no neuroprotective effect. The neuroprotection effect of naringenin was due to the inhibition of JUN phosphorylation in crush-injured retinal ganglion cells. Therefore, the citrus component naringenin provides neuroprotection through the inhibition of the JNK-JUN pathway by inhibiting JUN phosphorylation, indicating the potential application of citrus chemical components in the clinical therapy of traumatic optic nerve injuries.

scholarly journals Overexpression of Reticulon 3 enhances CNS axon regeneration and functional recovery after injury

2021 ◽  
Author(s):  
Zubair Ahmed ◽  
Sharif Alhajlah ◽  
Adam Thompson
Keyword(s):  
Spinal Cord ◽  
Optic Nerve ◽  
Neurite Outgrowth ◽  
Functional Recovery ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Dorsal Root Ganglion Neurons ◽  
Ganglion Neurons

CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-66. Here, we focused on RTN3 as its contribution in CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury.

scholarly journals Overexpression of Reticulon 3 Enhances CNS Axon Regeneration and Functional Recovery after Traumatic Injury

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2015
Author(s):  
Sharif Alhajlah ◽  
Adam M Thompson ◽  
Zubair Ahmed
Keyword(s):  
Spinal Cord ◽  
Optic Nerve ◽  
Neurite Outgrowth ◽  
Functional Recovery ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Dorsal Root Ganglion Neurons ◽  
Ganglion Neurons

CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-A. Here, we focused on RTN3 as its contribution to CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a well-characterised model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin, however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury.

scholarly journals Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing

2020 ◽  
Vol 27 (10) ◽  
pp. 2810-2827 ◽  
Author(s):  
Björn Friedhelm Vahsen ◽  
Vinicius Toledo Ribas ◽  
Jonas Sundermeyer ◽  
Alexander Boecker ◽  
Vivian Dambeck ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Axonal Degeneration ◽  
Dominant Negative ◽  
Focal Lesion ◽  
Pathological Feature ◽  
Nerve Crush ◽  
Cord Injury ◽  
Rat Cortical Neurons

Abstract Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes Kif1b and Ddit3. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.

scholarly journals SCYL1BP1 modulates neurite outgrowth and regeneration by regulating the Mdm2/p53 pathway

2012 ◽  
Vol 23 (23) ◽  
pp. 4506-4514 ◽  
Author(s):  
Yonghua Liu ◽  
Ying Chen ◽  
Xiang Lu ◽  
Youhua Wang ◽  
Yinong Duan ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Cortical Neurons ◽  
Axonal Regeneration ◽  
P53 Protein ◽  
Transcriptional Activator ◽  
Small Interfering Rnas ◽  
P53 Pathway ◽  
Neuronal Morphogenesis

SCY1-like 1–binding protein 1 (SCYL1BP1) is a newly identified transcriptional activator domain containing a protein with many unknown biological functions. Recently emerging evidence has revealed that it is a novel regulator of the p53 pathway, which is required for neurite outgrowth and regeneration. Here we present evidence that SCYL1BP1 inhibits nerve growth factor–mediated neurite outgrowth in PC12 cells and affects morphogenesis of primary cortical neurons by strongly decreasing the p53 protein level in vitro, all of which depends on SCYL1BP1's transcriptional activator domain. Exogenous p53 rescues neurite outgrowth and neuronal morphogenesis defects caused by SCYL1BP1. Furthermore, SCYL1BP1 can directly induce Mdm2 transcription, whereas inhibiting the function of Mdm2 by specific small interfering RNAs results in partial rescue of neurite outgrowth and neuronal morphogenesis defects induced by SCYL1BP1. In vivo experiments show that SCYL1BP1 can also depress axonal regeneration, whereas inhibiting the function of SCYL1BP1 by specific short hairpin RNA enhances it. Taken together, these data strongly suggested that SCYL1BP1 is a novel transcriptional activator in neurite outgrowth by directly modulating the Mdm2/p53-dependent pathway, which might play an important role in CNS development and axonal regeneration after injury.

scholarly journals Mesoscopic cortical network reorganization during recovery of partial optic nerve injury in GCaMP6s mice

2020 ◽  
Author(s):  
Marianne Groleau ◽  
Mojtaba Nazari-Ahangarkolaee ◽  
Matthieu P. Vanni ◽  
Jacqueline L. Higgins ◽  
Anne-Sophie Vézina Bédard ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Optic Nerve ◽  
Nerve Injury ◽  
Cortical Plasticity ◽  
Ganglion Cells ◽  
Wide Field ◽  
Optic Nerve Injury ◽  
Nerve Crush ◽  
Correlated Activity

AbstractAs the residual vision following a traumatic optic nerve injury can spontaneously recover over time, we explored the plasticity of cortical networks during the early post-optic nerve crush (ONC) phase. Using in vivo wide-field calcium imaging on awake Thy1-GCaMP6s mice, we characterized resting state and evoked cortical activity before, during, and 30 days after ONC. The recovery of monocular visual acuity and depth perception was evaluated at the same time points. Cortical responses to an LED flash decreased in the contralateral hemisphere in the primary visual cortex and in the secondary visual areas following the ONC, but was partially rescued between 3 and 5 days post-ONC, remaining stable thereafter. The connectivity between visual and non-visual regions was disorganized after the crush, as shown by a decorrelation, but correlated activity was restored 30 days after the injury. The number of surviving retinal ganglion cells dramatically dropped and remained low. At the behavioral level, the ONC resulted in visual acuity loss on the injured side and an increase in visual acuity with the non-injured eye. In conclusion, our results show a reorganization of connectivity between visual and associative cortical areas after an ONC, which is indicative of spontaneous cortical plasticity.

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