title: Exploiting mTOR signaling: a novel translatable treatment strategy for traumatic optic neuropathy?
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.
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Morgan-Warren
authors.forename: Martin
authors.initials: M
authors.lastname: Berry
authors.forename: Zubair
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Robert A H
authors.initials: RA
authors.lastname: Scott
authors.forename: Ann
authors.initials: A
authors.lastname: Logan
mesh_terms: D006801:Humans; D009416:Nerve Regeneration / Q000502:physiology; D020221:Optic Nerve Injuries / Q000503:physiopathology* / Q000628:therapy; D012165:Retinal Ganglion Cells / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D058570:TOR Serine-Threonine Kinases
keywords: axon regeneration; mTOR; optic nerve; retinal ganglion cells; traumatic optic neuropathy