scholarly journals Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 625
Author(s):  
Yang ◽  
Nguyen ◽  
Lin ◽  
Yarmishyn ◽  
Chen ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Optic Neuropathy ◽  
Ampa Receptors ◽  
Ganglion Cells ◽  
Genetic Disorder ◽  
Signal Transduction Pathway ◽  
Cellular Level ◽  
Scaffold Proteins ◽  
Patient Specific ◽  
Retinal Ganglion

The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs.

scholarly journals Protective Effects of Oroxylin A on Retinal Ganglion Cells in Experimental Model of Anterior Ischemic Optic Neuropathy

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 902
Author(s):  
Jia-Ying Chien ◽  
Shu-Fang Lin ◽  
Yu-Yau Chou ◽  
Chi-Ying F. Huang ◽  
Shun-Ping Huang
Keyword(s):  
Retinal Ganglion Cells ◽  
Optic Neuropathy ◽  
Ganglion Cells ◽  
Ischemic Injury ◽  
Anterior Ischemic Optic Neuropathy ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Ischemic Optic Neuropathy ◽  
Retinal Ganglion ◽  
Oroxylin A

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute vision loss in older people, and there is no effective therapy. The effect of the systemic or local application of steroids for NAION patients remains controversial. Oroxylin A (OA) (5,7-dihydroxy-6-methoxyflavone) is a bioactive flavonoid extracted from Scutellariae baicalensis Georgi. with various beneficial effects, including anti-inflammatory and neuroprotective effects. A previous study showed that OA promotes retinal ganglion cell (RGC) survival after optic nerve (ON) crush injury. The purpose of this research was to further explore the potential actions of OA in ischemic injury in an experimental anterior ischemic optic neuropathy (rAION) rat model induced by photothrombosis. Our results show that OA efficiently attenuated ischemic injury in rats by reducing optic disc edema, the apoptotic death of retinal ganglion cells, and the infiltration of inflammatory cells. Moreover, OA significantly ameliorated the pathologic changes of demyelination, modulated microglial polarization, and preserved visual function after rAION induction. OA activated nuclear factor E2 related factor (Nrf2) signaling and its downstream antioxidant enzymes NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1) in the retina. We demonstrated that OA activates Nrf2 signaling, protecting retinal ganglion cells from ischemic injury, in the rAION model and could potentially be used as a therapeutic approach in ischemic optic neuropathy.

The Photopic Negative Response evaluation in patients with Leber's hereditary optic neuropathy

2021 ◽  
pp. 216-219
Author(s):  
M.S. Shmelkova ◽  
◽  
N.L. Sheremet ◽  
I.A. Ronzina ◽  
N.A. Andreeva ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Retinal Ganglion Cells ◽  
Optic Neuropathy ◽  
Ganglion Cells ◽  
Negative Response ◽  
Photopic Negative Response ◽  
Control Group ◽  
Retinal Ganglion ◽  
Leber's Hereditary Optic Neuropathy ◽  
Hereditary Optic Neuropathy

Purpose. To assess the retinal ganglion cells function in patients with Leber's hereditary optic neuropathy (LHON) by registering the photopic negative response (PhNR) while the photopic electroretinography is performed. Material and methods. 14 patients with different LHON mutations and 9 healthy individuals were examined. A standard ophtalmological examination was performed, including visual fields, spectral optical coherence tomography, photopic electroretinography and PhNR tests. Results. Significant differences in the PhNR latency (68.4±4.01/64.28±5.37, p<0,01) and the PhNR amplitude (21.5±9.34/32.72±12.73, p<0,003) were revealed in patients with LHON and the control group. The study revealed significant differences between the PhNR latency (р<0.01) and the PhNR amplitude (р<0.008) in patients with visual acuity (VA) ≤ 0.1 and the control group, and between the PhNR amplitude in patients with VA≥0.13 and the control group (р<0.05). There were found significant correlations between the PhNR parameters and visual acuity, mean sensitivity, RNFL and GCC thickness. A strong positive correlation was found between the PhNR amplitude and the GCC thickness in patients with VA≥0.3. Conclusion. The PhNR parameters reflect the retinal ganglion cells function in patients with LHON and correlate with RNFL and GCC structural changes. Key words: Leber hereditary optic neuropathy, mitochondrial optical neuropathies, retinal ganglion cell, photopic negative response, PhNR.

scholarly journals Leber Hereditary Optic Neuropathy: Review of Treatment and Management

2021 ◽  
Vol 12 ◽  
Author(s):  
Rabih Hage ◽  
Catherine Vignal-Clermont
Keyword(s):  
Retinal Ganglion Cells ◽  
Optic Neuropathy ◽  
Visual Loss ◽  
Ganglion Cells ◽  
Management Strategies ◽  
Retinal Ganglion ◽  
Leber Hereditary Optic Neuropathy ◽  
Efficient Treatment ◽  
Loss Of Vision ◽  
Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease that specifically targets the retinal ganglion cells by reducing their ability to produce enough energy to sustain. The mutations of the mitochondrial DNA that cause LHON are silent until an unknown trigger causes bilateral central visual scotoma. After the onset of loss of vision, most patients experience progressive worsening within the following months. Few of them regain some vision after a period of ~1 year. Management of LHON patients has been focused on understanding the triggers of the disease and its pathophysiology to prevent the onset of visual loss in a carrier. Medical treatment is recommended once visual loss has started in at least one eye. Research evaluated drugs that are thought to be able to restore the mitochondrial electron transport chain of the retinal ganglion cells. Significant advances were made in evaluating free radical cell scavengers and gene therapy as potential treatments for LHON. Although encouraging the results of clinical trial have been mixed in stopping the worsening of visual loss. In patients with chronic disease of over 1 year, efficient treatment that restores vision is yet to be discovered. In this review, we summarize the management strategies for patients with LHON before, during, and after the loss of vision, explain the rationale and effectiveness of previous and current treatments, and report findings about emerging treatments.

Sign in / Sign up

Export Citation Format

Share Document