The Role of the mTOR Pathway in Treating Spinal Cord Injury for Neuron Survival and Axonal Growth
Background: Spinal cord injury (SCI) is a “destructive neurological and pathological state that causes major motor, sensory, and autonomic dysfunctions”.1 Primary spinal cord injury is caused by direct blunt trauma to the spinal cord either from direct force or by impingement from vertebral fragments. Primary injury will most likely never be fully avoidable without unrealistic massive oversight and safety practices in all aspects of life. However, “secondary injury” is a process triggered by SCI and leads to a cascade of events that produces further damage to the spinal cord. Recent therapeutic interventions are focused on secondary injury prevention or neural tissue regeneration.2 During secondary injury, oligodendrocytes may incur damage due to glutamate excitotoxicity, reactive oxygen and nitrogen species, and certain cytokines or extracellular signals that induce apoptosis. This oligodendrocyte necrosis and apoptosis directly leads to the loss of myelin and axon degeneration.1 By targeting this process, researchers may be able to prevent unnecessary secondary injury. The focus of this search was on the mTOR (mammalian target of rapamycin) pathway in its relation to myelination and demyelination following SCI.
Objective: The purpose of this literature review was to determine the current knowledge of the modulation of mTOR activity post-SCI and the associated differential recovery.
Search Methods: An online search using the PubMed database was carried out searching literature from 2018-2023 using keywords such as: “mTOR”, “oligodendrocyte”, “spinal cord injury”, “myelination”, “demyelination”, etc.
Results: Studies found that mTOR and phosphorylated (activated) mTOR is naturally upregulated following SCI.5 This suggests that mTOR plays some role in the natural body response to neural trauma within the spinal cord. In that same animal model, researchers found that oligodendrocyte proliferation was associated with mTOR activation via a compound known as SC79 (verified by western blot analysis of downstream proteins in the mTOR pathway).5 In a separate model using zebrafish mTOR knockouts, researchers found that mTOR was also involved in myelin stabilization.7 These findings support the idea of upregulating mTOR following SCI. In a different study, rapamycin was used to downregulate mTOR following SCI. This rat model showed greater white matter preservation, assessed using immunofluorescence of myelin proteins.6 In one study where mTOR was also inhibited using rapamycin and pp242, researchers found an increase in autophagy related proteins when treated with these inhibitors following SCI. These elevated levels were also associate with better structural and functional recovery in the rats.8
Conclusion: Activating the mTOR pathway after spinal cord injury can be beneficial, leading to greater levels of myelination in oligodendrocytes and oligodendrocyte proliferation. However, there seems to be another body of evidence with positive results in white matter preservation and functional recovery. This review revealed that there needs to be more work done in this field. The link between mTOR and the secondary injury modulation or prevention is not clear now. Future directions for the field should focus on possible timings of different interventions, such as upregulating mTOR at first and then downregulating at a later point.
- Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020;21(20):7533. Published 2020 Oct 13. doi:10.3390/ijms21207533
- Karsy M, Hawryluk G. Modern Medical Management of Spinal Cord Injury. Curr Neurol Neurosci Rep. 2019;19(9):65. Published 2019 Jul 30. doi:10.1007/s11910-019-0984-1
- Kirshblum S, Snider B, Eren F, Guest J. Characterizing Natural Recovery after Traumatic Spinal Cord Injury. J Neurotrauma. 2021;38(9):1267-1284. doi:10.1089/neu.2020.7473
- Spinal Cord Injury. AANS. https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Spinal-Cord-Injury. Accessed February 6, 2023.
- Ge C, Liu D, Sun Y. The promotive effect of activation of the Akt/mTOR/p70S6K signaling pathway in oligodendrocytes on nerve myelin regeneration in rats with spinal cord injury [published online ahead of print, 2020 Dec 21]. Br J Neurosurg. 2020;1-9. doi:10.1080/02688697.2020.1862056
- Liu J, Li R, Huang Z, et al. Rapamycin Preserves Neural Tissue, Promotes Schwann Cell Myelination and Reduces Glial Scar Formation After Hemi-Contusion Spinal Cord Injury in Mice. Front Mol Neurosci. 2021;13:574041. Published 2021 Jan 22. doi:10.3389/fnmol.2020.574041
- Fedder-Semmes KN, Appel B. The Akt-mTOR Pathway Drives Myelin Sheath Growth by Regulating Cap-Dependent Translation. J Neurosci. 2021;41(41):8532-8544. doi:10.1523/JNEUROSCI.0783-21.2021
- Vargova I, Machova Urdzikova L, Karova K, et al. Involvement of mTOR Pathways in Recovery from Spinal Cord Injury by Modulation of Autophagy and Immune Response. Biomedicines. 2021;9(6):593. Published 2021 May 24. doi:10.3390/biomedicines9060593
- Musah AS, Brown TL, Jeffries MA, et al. Mechanistic Target of Rapamycin Regulates the Oligodendrocyte Cytoskeleton during Myelination. J Neurosci. 2020;40(15):2993-3007. doi:10.1523/JNEUROSCI.1434-18.2020