-
Neuroreport May 2023To clarify whether fucoxanthin plays a protective role and regulates parkin-mediated mitophagy on retinal ganglion cells (RGCs) against glutamate excitotoxicity.
OBJECTIVE
To clarify whether fucoxanthin plays a protective role and regulates parkin-mediated mitophagy on retinal ganglion cells (RGCs) against glutamate excitotoxicity.
METHODS
The excitotoxicity model of primary RGCs was carried out with glutamate. Mitochondrial membrane potential was measured by JC-1 kit (Abcam, USA). The apoptotic rate and cytotoxicity were detected by Hoechst staining and lactate dehydrogenase (LDH) kit (Takara, Japan). Mitochondria was assessed by MitoTracker staining and confocal microscopy. The mRNA levels and protein expression levels of Bax, Bcl-2, parkin, optineurin, LC3, and LAMP1 in RGCs were analyzed by quantitative PCR and immunoblotting. Finally, the mitochondrial health score and mitophagy were assessed by transmission electron microscopy.
RESULTS
Fucoxanthin increased the mitochondrial membrane potential of RGCs, reduced cytotoxicity, and decreased apoptosis in RGCs under glutamate excitotoxicity. It also enhanced expression levels of parkin, optineurin, and LAMP1, and upgraded the ratio of LC3-II to LC3-I. Meanwhile, fucoxanthin increased LC3 and MitoTracker co-localization staining. In addition, up-regulated mitochondrial health score, and the number of autophagosomes and mitophagosomes were observed in fucoxanthin-treated RGCs under glutamate excitotoxicity.
CONCLUSION
Fucoxanthin may exert its neuroprotective effect on RGCs via promoting parkin-mediated mitophagy under glutamate excitotoxicity. The neuroprotective effect of fucoxanthin in glaucomatous neurodegeneration and ocular diseases characterized by impaired mitophagy warrants further investigation.
Topics: Retinal Ganglion Cells; Glutamic Acid; Mitophagy; Neuroprotective Agents; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 37096783
DOI: 10.1097/WNR.0000000000001902 -
International Journal of Molecular... Jul 2021Retinal ganglion cells (RGCs) are a population of neurons of the central nervous system (CNS) extending with their soma to the inner retina and with their axons to the... (Review)
Review
Retinal ganglion cells (RGCs) are a population of neurons of the central nervous system (CNS) extending with their soma to the inner retina and with their axons to the optic nerve. Glaucoma represents a group of neurodegenerative diseases where the slow progressive death of RGCs results in a permanent loss of vision. To date, although Intra Ocular Pressure (IOP) is considered the main therapeutic target, the precise mechanisms by which RGCs die in glaucoma have not yet been clarified. In fact, Primary Open Angle Glaucoma (POAG), which is the most common glaucoma form, also occurs without elevated IOP. This present review provides a summary of some pathological conditions, i.e., axonal transport blockade, glutamate excitotoxicity and changes in pro-inflammatory cytokines along the RGC projection, all involved in the glaucoma cascade. Moreover, neuro-protective therapeutic approaches, which aim to improve RGC degeneration, have also been taken into consideration.
Topics: Animals; Axonal Transport; Axons; Disease Models, Animal; Glaucoma; Humans; Neuroprotection; Optic Nerve; Retinal Ganglion Cells
PubMed: 34360760
DOI: 10.3390/ijms22157994 -
Cells Nov 2023The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT)...
The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in , , and knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.
Topics: Animals; Intraocular Pressure; Retinal Ganglion Cells; Inflammasomes; Ocular Hypertension; Glaucoma
PubMed: 37998361
DOI: 10.3390/cells12222626 -
Nature Apr 2021The output of the retina is organized into many detector grids, called 'mosaics', that signal different features of visual scenes to the brain. Each mosaic comprises a...
The output of the retina is organized into many detector grids, called 'mosaics', that signal different features of visual scenes to the brain. Each mosaic comprises a single type of retinal ganglion cell (RGC), whose receptive fields tile visual space. Many mosaics arise as pairs, signalling increments (ON) and decrements (OFF), respectively, of a particular visual feature. Here we use a model of efficient coding to determine how such mosaic pairs should be arranged to optimize the encoding of natural scenes. We find that information is maximized when these mosaic pairs are anti-aligned, meaning that the distances between the receptive field centres across mosaics are greater than expected by chance. We tested this prediction across multiple receptive field mosaics acquired using large-scale measurements of the light responses of rat and primate RGCs. ON and OFF RGC pairs with similar feature selectivity had anti-aligned receptive field mosaics, consistent with this prediction. ON and OFF RGC types that encode distinct features have independent mosaics. These results extend efficient coding theory beyond individual cells to predict how populations of diverse types of RGC are spatially arranged.
Topics: Animals; Female; Macaca; Male; Models, Neurological; Rats; Rats, Long-Evans; Retina; Retinal Ganglion Cells; Visual Fields
PubMed: 33692544
DOI: 10.1038/s41586-021-03317-5 -
Neurobiology of Disease Jan 2021Pathological accumulations of amyloid-beta (Aβ) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown....
Pathological accumulations of amyloid-beta (Aβ) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aβ protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aβ exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection. Pathology was not limited to the retina, but propagated into other areas of the central nervous system. Microgliosis spread throughout the retinal projection (retina, ON, and SC), with multiplex protein quantitation demonstrating an increase in endogenously produced Aβ in the ON and SC corresponding to the injected retinas. Surprisingly, this pathology spread to the opposite side, with unilateral Aβ eye injections driving increased Aβ levels, neuroinflammation, and RGC death in the opposite, un-injected retinal projection. As Aβ-mediated microglial activation has been shown to propagate Aβ pathology, we also investigated the role of the Aβ-binding microglial scavenger receptor CD36 in this pathology. Transgenic mice lacking the CD36 receptor were resistant to Aβ-induced inflammation and RGC death up to 2 weeks following exposure. These results indicate that Aβ pathology drives regional neuropathology in the retina and does not remain isolated to the affected eye, but spreads throughout the nervous system. Further, CD36 may serve as a promising target to prevent Aβ-mediated inflammatory damage.
Topics: Amyloid beta-Protein Precursor; Animals; CD36 Antigens; Female; Gliosis; Humans; Intravitreal Injections; Male; Mice, Inbred C57BL; Microglia; Optic Nerve; Retina; Retinal Ganglion Cells; Superior Colliculi; Mice
PubMed: 33122075
DOI: 10.1016/j.nbd.2020.105146 -
Clinical & Experimental Optometry Sep 2020Glaucoma is a neurodegenerative disease characterised by progressive damage to the retinal ganglion cells (RGCs), the output neurons of the retina. RGCs are a... (Review)
Review
Glaucoma is a neurodegenerative disease characterised by progressive damage to the retinal ganglion cells (RGCs), the output neurons of the retina. RGCs are a heterogenous class of retinal neurons which can be classified into multiple types based on morphological, functional and genetic characteristics. This review examines the body of evidence supporting type-specific vulnerability of RGCs in glaucoma and explores potential mechanisms by which this might come about. Studies of donor tissue from glaucoma patients have generally noted greater vulnerability of larger RGC types. Models of glaucoma induced in primates, cats and mice also show selective effects on RGC types - particularly OFF RGCs. Several mechanisms may contribute to type-specific vulnerability, including differences in the expression of calcium-permeable receptors (for example pannexin-1, P2X7, AMPA and transient receptor potential vanilloid receptors), the relative proximity of RGCs and their dendrites to blood supply in the inner plexiform layer, as well as differing metabolic requirements of RGC types. Such differences may make certain RGCs more sensitive to intraocular pressure elevation and its associated biomechanical and vascular stress. A greater understanding of selective RGC vulnerability and its underlying causes will likely reveal a rich area of investigation for potential treatment targets.
Topics: Disease Progression; Glaucoma; Humans; Intraocular Pressure; Retinal Ganglion Cells; Severity of Illness Index
PubMed: 31838755
DOI: 10.1111/cxo.13031 -
International Journal of Molecular... Sep 2019Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially... (Review)
Review
Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially affect rods and cones, situated in the outer retina. For many years it was assumed that these diseases did not spread to the inner retina. However, it is now known that photoreceptor loss leads to an unavoidable chain of events that cause neurovascular changes in the retina including migration of retinal pigment epithelium cells, formation of "subretinal vascular complexes", vessel displacement, retinal ganglion cell (RGC) axonal strangulation by retinal vessels, axonal transport alteration and, ultimately, RGC death. These events are common to all photoreceptor degenerations regardless of the initial trigger and thus threaten the outcome of photoreceptor substitution as a therapeutic approach, because with a degenerating inner retina, the photoreceptor signal will not reach the brain. In conclusion, therapies should be applied early in the course of photoreceptor degeneration, before the remodeling process reaches the inner retina.
Topics: Animals; Axonal Transport; Cell Death; Humans; Photoreceptor Cells, Vertebrate; Retinal Degeneration; Retinal Ganglion Cells; Retinal Pigment Epithelium; Retinal Vessels
PubMed: 31546829
DOI: 10.3390/ijms20184649 -
International Ophthalmology Clinics 2019
Review
Topics: Animals; Cell Death; Fluorescein Angiography; Fundus Oculi; Glaucoma; Humans; Intraocular Pressure; Retinal Ganglion Cells; Tomography, Optical Coherence
PubMed: 31569133
DOI: 10.1097/IIO.0000000000000285 -
Current Biology : CB Jul 2022Mice detect decreases in illumination in dim light near the visual threshold with OFF retinal ganglion cells.
Mice detect decreases in illumination in dim light near the visual threshold with OFF retinal ganglion cells.
Topics: Animals; Lighting; Mice; Photic Stimulation; Retinal Ganglion Cells; Vision, Ocular; Visual Perception
PubMed: 35820384
DOI: 10.1016/j.cub.2022.06.001 -
PloS One 2022The primate fovea is specialized for high acuity chromatic vision, with the highest density of cone photoreceptors and a disproportionately large representation in...
The primate fovea is specialized for high acuity chromatic vision, with the highest density of cone photoreceptors and a disproportionately large representation in visual cortex. The unique visual properties conferred by the fovea are conveyed to the brain by retinal ganglion cells, the somas of which lie at the margin of the foveal pit. Microelectrode recordings of these centermost retinal ganglion cells have been challenging due to the fragility of the fovea in the excised retina. Here we overcome this challenge by combining high resolution fluorescence adaptive optics ophthalmoscopy with calcium imaging to optically record functional responses of foveal retinal ganglion cells in the living eye. We use this approach to study the chromatic responses and spatial transfer functions of retinal ganglion cells using spatially uniform fields modulated in different directions in color space and monochromatic drifting gratings. We recorded from over 350 cells across three Macaca fascicularis primates over a time period of weeks to months. We find that the majority of the L vs. M cone opponent cells serving the most central foveolar cones have spatial transfer functions that peak at high spatial frequencies (20-40 c/deg), reflecting strong surround inhibition that sacrifices sensitivity at low spatial frequencies but preserves the transmission of fine detail in the retinal image. In addition, we fit to the drifting grating data a detailed model of how ganglion cell responses draw on the cone mosaic to derive receptive field properties of L vs. M cone opponent cells at the very center of the foveola. The fits are consistent with the hypothesis that foveal midget ganglion cells are specialized to preserve information at the resolution of the cone mosaic. By characterizing the functional properties of retinal ganglion cells in vivo through adaptive optics, we characterize the response characteristics of these cells in situ.
Topics: Animals; Fovea Centralis; Macaca fascicularis; Retina; Retinal Cone Photoreceptor Cells; Retinal Ganglion Cells
PubMed: 36445926
DOI: 10.1371/journal.pone.0278261