Radiation-induced optic neuropathy (RION) is a devastating complication following external beam radiation therapy (EBRT) that leads to acute vision loss. To date, no efficient, available treatment for this complication, due partly to the lack of understanding regarding the developmental processes behind RION. Here, we report radiation caused changes in mitochondrial dynamics by regulating the mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission-1 (Fis1). Concurrent with an excessive production of reactive oxygen species (ROS), both neuronal injury and visual dysfunction resulted. Further, our findings delineate an important mechanism by which cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of Drp1 (Ser616) regulates defects in mitochondrial dynamics associated with neuronal injury in the development of RION. Both the pharmacological inhibition of Cdk5 by roscovitine and the inhibition of Drp1 by mdivi-1 inhibited mitochondrial fission and the production of ROS associated with radiation-induced neuronal loss. Taken together, these findings may have clinical significance in preventing the development of RION.

/pdf/cdk5-mediated-drp1-phosphorylation-drives-mitochondrial-1cjfm8p83e.pdf

Cdk5-mediated Drp1 phosphorylation drives mitochondrial defects and neuronal apoptosis in radiation-induced optic neuropathy.

Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets. Only 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR. A number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue-specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure.

/pdf/optic-nerve-crush-induces-spatial-and-temporal-gene-2w1b7lyelw.pdf

Optic nerve crush induces spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice.

Purpose: Pathophysiological events in the retinal ganglion cell layer (GCL) are a prominent feature of several optic neuropathies including glaucoma. The purpose of this study was to identify and catalog genes whose expression in the human retina is restricted to the GCL. Methods: Laser capture microdissection (LCM) technology was used to isolate tissue from the perimacular retina of three human donors without retinal or optic nerve disease. RNA was isolated from the (1) retinal GCL and (2) the inner and outer nuclear layers of the same retina, and the gene expression profiles of both fractions were determined using Affymetrix Hu133Plus 2.0 GeneChips. Data were analyzed to identify those genes whose expression is substantially more prevalent in the GCL when compared to the outer retinal layers. Differential expression of selected genes was confirmed by realtime PCR and immunohistochemistry. Results: The results show that mRNA levels of previously described ganglion cell markers, e.g. the neurofilament genes (NEFH, NEF3, or NEFL) and the Brn3a transcription factor (POU4F1), were highly enriched in the isolated GCL fraction. In contrast, transcripts for genes associated with phototransduction (RHO), photoreceptor development (NR2E3), or interphotoreceptor matrix constituents (IMPG1) were nearly absent from the GCL fraction. Using bioinformatics approaches over 80 genes were identified whose expression in the human retina appears to be limited to the GCL. Conclusions: We have successfully used LCM technology to generate gene expression profiles of highly enriched GCL fractions of the normal human retina. These data not only provide clues to the normal function of retinal ganglion cells but also serve as a resource in the development of ganglion cell specific markers or transfection vectors, and the identification of candidate genes for hereditary forms of glaucoma.

https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/110567/1/T200601560.pdf

Gene expression profile of the adult human retinal ganglion cell layer

PURPOSE Optic nerve injury has been found to be dramatically reduced in a genetic mouse glaucoma model following exposure to sublethal, head-only irradiation. In this study, the same radiation treatment was used prior to experimental induction of elevated intraocular pressure (IOP) to determine if radiation is neuroprotective in another glaucoma model. METHODS Episcleral vein injection of hypertonic saline was used to elevate IOP unilaterally in two groups of rats: (1) otherwise untreated and (2) radiation pretreated, n > 25/group. Intraocular pressure histories were collected for 5 weeks, when optic nerves were prepared and graded for injury. Statistical analyses were used to compare IOP history and nerve injury. The density of microglia and macrophages in two nerve head regions was determined by Iba1 immunolabeling. RESULTS Mean and peak IOP elevations were not different between the two glaucoma model groups. Mean optic nerve injury grades were not different in glaucoma model optic nerves and were equivalent to approximately 35% of axons degenerating. Nerves selected for lower mean or peak IOP elevations did not differ in optic nerve injury. Similarly, nerves selected for lower injury grade did not differ in IOP exposure. By multiple regression modeling, nerve injury grade was most significantly associated with mean IOP (P < 0.002). There was no significant effect of radiation treatment. Iba1+ cell density was not altered by radiation treatment. CONCLUSIONS In contrast to previous observations in a mouse genetic glaucoma model, head-only irradiation offers the adult rat optic nerve no protection from optic nerve degeneration due to chronic, experimentally induced IOP elevation.

/pdf/radiation-pretreatment-does-not-protect-the-rat-optic-nerve-48q8cutqy9.pdf

Radiation pretreatment does not protect the rat optic nerve from elevated intraocular pressure-induced injury.

Quantitative assessment of optic nerve in patients with Leber’s hereditary optic neuropathy using reduced field-of-view diffusion tensor imaging

Department ofOphthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, P.R. ChinaPurpose: To obtain and analyze early retinal changes at the molecular level 24 h after a radiation injury to the ipsilateralintraorbital nerve using gamma knife surgery (GKS), and to examine the morphological changes in bilateral optic nerves.Methods: Unilateral intraorbital optic nerves of three rhesus macaques were treated by GKS with irradiated doses of 15Gy, while contralateral optic nerves and retinas served as the control. Gene expression profiles of the control and affectedretinas were analyzed with Affymetrix Rhesus Macaque Genome arrays. To verify the results, a quantitative real-timepolymerase chain reaction (qRT–PCR) was performed to test the expression patterns of five function-known genes.Morphological changes in the bilateral optic nerves were examined using a transmission electron microscope (TEM) andlight microscopy. The glial cell reaction in bilateral optic nerves was studied using immunohistochemistry.Results: Of the probe sets, 1,597 (representing 1,081 genes) met the criteria for differential expression, of which 82 geneswere significantly up-or down-regulated in treated retinas. There was prominent upregulation of genes associated withglial cell activation in the treated retina. Genes related to an early inflammatory reaction and to cell death were alsosignificantly regulated in response to a radiation injury to the intraorbital optic nerve. In contrast, the messenger ribonucleicacid (mRNA) expression levels of retinal ganglion cell (RGC)-specific genes were low. Morphologically, cytoplasmicprocesses of astrocytes in treated nerves were shorter than those of the control and were not straight, while also beingaccompanied by decreased GFAP immunostaining. More oligodendrocytes and inflammatory cells were apparent intreated nerves than in the control. In addition, swollen mitochondria and slight chromation condensation could be seen inthe glial cells of treated nerves.Conclusions: We conclude that the current irradiated dose of 15 Gy was sufficient to lead to a radiation injury of the opticnerve and retina. Several transcripts deregulated in retinas after a radiation injury play a key role in radiation-inducedneurogenic visual loss, especially for genes associated with RGC, glial cell, and cell death. Glial cells in optic nervesmight be the primary target of a radiation injury in the optic nerve.

/pdf/retinal-whole-genome-microarray-analysis-and-early-16gtmyyv78.pdf

Retinal whole genome microarray analysis and early morphological changes in the optic nerves of monkeys after an intraorbital nerve irradiated injury.

Magnetic resonance diffusion tensor imaging study of rhesus optic nerve radiation injury caused by a single dose/fractionation scheme stereotactic radiosurgery at an early stage

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Retinal whole genome microarray analysis and early morphological changes in the optic nerves of monkeys after an intraorbital nerve irradiated injury.

Magnetic resonance diffusion tensor imaging study of rhesus optic nerve radiation injury caused by a single dose/fractionation scheme stereotactic radiosurgery at an early stage