» Articles » PMID: 19176818

The Rheb-mTOR Pathway is Upregulated in Reactive Astrocytes of the Injured Spinal Cord

Overview
Journal J Neurosci
Specialty Neurology
Date 2009 Jan 30
PMID 19176818
Citations 80
Authors
Affiliations
Soon will be listed here.
Abstract

Astrocytes in the CNS respond to tissue damage by becoming reactive. They migrate, undergo hypertrophy, and form a glial scar that inhibits axon regeneration. Therefore, limiting astrocytic responses represents a potential therapeutic strategy to improve functional recovery. It was recently shown that the epidermal growth factor (EGF) receptor is upregulated in astrocytes after injury and promotes their transformation into reactive astrocytes. Furthermore, EGF receptor inhibitors were shown to enhance axon regeneration in the injured optic nerve and promote recovery after spinal cord injury. However, the signaling pathways involved were not elucidated. Here we show that in cultures of adult spinal cord astrocytes EGF activates the mTOR pathway, a key regulator of astrocyte physiology. This occurs through Akt-mediated phosphorylation of the GTPase-activating protein Tuberin, which inhibits Tuberin's ability to inactivate the small GTPase Rheb. Indeed, we found that Rheb is required for EGF-dependent mTOR activation in spinal cord astrocytes, whereas the Ras-MAP kinase pathway does not appear to be involved. Moreover, astrocyte growth and EGF-dependent chemoattraction were inhibited by the mTOR-selective drug rapamycin. We also detected elevated levels of activated EGF receptor and mTOR signaling in reactive astrocytes in vivo in an ischemic model of spinal cord injury. Furthermore, increased Rheb expression likely contributes to mTOR activation in the injured spinal cord. Interestingly, injured rats treated with rapamycin showed reduced signs of reactive gliosis, suggesting that rapamycin could be used to harness astrocytic responses in the damaged nervous system to promote an environment more permissive to axon regeneration.

Citing Articles

AKT2 modulates astrocytic nicotine responses .

Lombardi A, Wong H, Bower M, Milstead R, Borski C, Schmitt E bioRxiv. 2024; .

PMID: 38854016 PMC: 11160815. DOI: 10.1101/2024.05.31.596856.


Impacts of PI3K/protein kinase B pathway activation in reactive astrocytes: from detrimental effects to protective functions.

Perez-Nunez R, Gonzalez M, Avalos A, Leyton L Neural Regen Res. 2024; 20(4):1031-1041.

PMID: 38845231 PMC: 11438337. DOI: 10.4103/NRR.NRR-D-23-01756.


Non-canonical retinoid signaling in neural development, regeneration and synaptic function.

Piazza A, Carlone R, Spencer G Front Mol Neurosci. 2024; 17:1371135.

PMID: 38516042 PMC: 10954794. DOI: 10.3389/fnmol.2024.1371135.


FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders.

Lui A, Vanleuven J, Perekopskiy D, Liu D, Xu D, Alzayat O Pharmaceuticals (Basel). 2022; 15(12).

PMID: 36558997 PMC: 9784968. DOI: 10.3390/ph15121546.


Endothelin-1, over-expressed in SOD1 mice, aggravates injury of NSC34-hSOD1G93A cells through complicated molecular mechanism revealed by quantitative proteomics analysis.

Zhang Y, Chen L, Li Z, Li D, Wu Y, Guo Y Front Cell Neurosci. 2022; 16:1069617.

PMID: 36531135 PMC: 9752095. DOI: 10.3389/fncel.2022.1069617.


References
1.
David G, Bai X, Van der Schueren B, Cassiman J, Van Den Berghe H . Developmental changes in heparan sulfate expression: in situ detection with mAbs. J Cell Biol. 1992; 119(4):961-75. PMC: 2289686. DOI: 10.1083/jcb.119.4.961. View

2.
Bhaskar P, Hay N . The two TORCs and Akt. Dev Cell. 2007; 12(4):487-502. DOI: 10.1016/j.devcel.2007.03.020. View

3.
Bai X, Ma D, Liu A, Shen X, Wang Q, Liu Y . Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science. 2007; 318(5852):977-80. DOI: 10.1126/science.1147379. View

4.
Franz D, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G . Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006; 59(3):490-8. DOI: 10.1002/ana.20784. View

5.
Irie H, Pearline R, Grueneberg D, Hsia M, Ravichandran P, Kothari N . Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol. 2005; 171(6):1023-34. PMC: 2171329. DOI: 10.1083/jcb.200505087. View