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Abstract
Retinal ganglion cell (RGC) death and a failure of axon regeneration contribute to the profound visual loss experienced by patients after traumatic optic neuropathy (TON), for which there are no effective treatments. Experimental manipulations of cellular signaling pathways in animal models have demonstrated that neuronal survival and axon regeneration in the mature central nervous system (CNS) are possible, and increased understanding of the molecular basis of prosurvival and regenerative signals has led to the identification of candidate targets for novel therapeutic strategies. The axogenic pathway is activated sequentially, after growth factor/receptor binding, through phosphoinositide-3-kinase (PI3K) and the downstream serine/threonine kinase Akt. Akt is a nodal point for the regulation of growth cone dynamics by glycogen synthase kinase (GSK3β) and axon protein synthesis/RGC survival by the mammalian target of rapamycin (mTOR). The mTOR signaling pathway has a pivotal role in numerous cellular processes. It is active during development, but downregulated in the mature CNS and further suppressed by axonal injury, and experimental upregulation of mTOR signaling promotes RGC survival and axon regeneration after optic nerve crush injury. However, several translational challenges remain, including understanding the regulatory mechanisms of axotomy-induced mTOR and GSK3β signaling, and the disparity between the RGC survival and axon regenerative effects. In this review, we explore the molecular basis of RGC regenerative failure and assess the potential for manipulations of mTOR signaling as a novel translatable treatment for TON.
Original language | English |
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Pages (from-to) | 6903-16 |
Number of pages | 14 |
Journal | Investigative Ophthalmology & Visual Science (IOVS) |
Volume | 54 |
Issue number | 10 |
DOIs | |
Publication status | Published - 2013 |
Keywords
- Humans
- Nerve Regeneration
- Optic Nerve Injuries
- Retinal Ganglion Cells
- Signal Transduction
- TOR Serine-Threonine Kinases
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- 1 Finished
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Development of a Small Molecule Combinatorial Treatment for RGC Survival and Axon Regeneration to Restore Sight After Optic Neuropathy
Logan, A. & Morgan-Warren, P.
1/09/12 → 31/08/15
Project: Research Councils