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Neural Regeneration Research Feb 2025Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and...
Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma, following a growing understanding of the molecular underpinnings of their development. This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches, focusing on the activation of transcription factor EB. Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies, such as exercise, calorie restriction, rapamycin, and metformin, in patients and animal models of these common retinal diseases. The review critically assesses the role of transcription factor EB in retinal biology during aging, its neuroprotective effects, and its therapeutic potential for retinal disorders. The impact of transcription factor EB on retinal aging is cell-specific, influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways. In vascular endothelial cells, transcription factor EB controls important processes, including endothelial cell proliferation, endothelial tube formation, and nitric oxide levels, thereby influencing the inner blood-retinal barrier, angiogenesis, and retinal microvasculature. Additionally, transcription factor EB affects vascular smooth muscle cells, inhibiting vascular calcification and atherogenesis. In retinal pigment epithelial cells, transcription factor EB modulates functions such as autophagy, lysosomal dynamics, and clearance of the aging pigment lipofuscin, thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization. These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis, neuronal synapse plasticity, energy metabolism, microvasculature, and inflammation, ultimately offering protection against retinal aging and diseases. The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases. Therefore, it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.
PubMed: 38819040
DOI: 10.4103/NRR.NRR-D-23-02033 -
Stem Cell Research & Therapy May 2024X-linked juvenile retinoschisis (XLRS) is an inherited disease caused by RS1 gene mutation, which leads to retinal splitting and visual impairment. The mechanism of...
BACKGROUND
X-linked juvenile retinoschisis (XLRS) is an inherited disease caused by RS1 gene mutation, which leads to retinal splitting and visual impairment. The mechanism of RS1-associated retinal degeneration is not fully understood. Besides, animal models of XLRS have limitations in the study of XLRS. Here, we used human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) to investigate the disease mechanisms and potential treatments for XLRS.
METHODS
hiPSCs reprogrammed from peripheral blood mononuclear cells of two RS1 mutant (E72K) XLRS patients were differentiated into ROs. Subsequently, we explored whether RS1 mutation could affect RO development and explore the effectiveness of RS1 gene augmentation therapy.
RESULTS
ROs derived from RS1 (E72K) mutation hiPSCs exhibited a developmental delay in the photoreceptor, retinoschisin (RS1) deficiency, and altered spontaneous activity compared with control ROs. Furthermore, the delays in development were associated with decreased expression of rod-specific precursor markers (NRL) and photoreceptor-specific markers (RCVRN). Adeno-associated virus (AAV)-mediated gene augmentation with RS1 at the photoreceptor immature stage rescued the rod photoreceptor developmental delay in ROs with the RS1 (E72K) mutation.
CONCLUSIONS
The RS1 (E72K) mutation results in the photoreceptor development delay in ROs and can be partially rescued by the RS1 gene augmentation therapy.
Topics: Retinoschisis; Humans; Induced Pluripotent Stem Cells; Eye Proteins; Genetic Therapy; Organoids; Mutation; Retina; Male; Cell Differentiation
PubMed: 38816767
DOI: 10.1186/s13287-024-03767-4 -
Frontiers in Molecular Neuroscience 2024The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual... (Review)
Review
The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual stimuli. A-kinase anchoring proteins (AKAPs), known for binding protein kinase A (PKA), contribute to the specificity and efficiency of retinal signaling. They play multifaceted roles in various retinal cell types, influencing photoreceptor sensitivity, neurotransmitter release in bipolar cells, and the integration of visual information in ganglion cells. AKAPs like AKAP79/150 and AKAP95 exhibit distinct subcellular localizations, impacting synaptic transmission and receptor sensitivity in photoreceptors and bipolar cells. Furthermore, AKAPs are involved in neuroprotective mechanisms and axonal degeneration, particularly in retinal ganglion cells. In particular, AKAP6 coordinates stress-specific signaling and promotes neuroprotection following optic nerve injury. As our review underscores the therapeutic potential of targeting AKAP signaling complexes for retinal neuroprotection and enhancement, it acknowledges challenges in developing selective drugs that target complex protein-protein interactions. Overall, this exploration of AKAPs provides valuable insights into the intricacies of retinal signaling, offering a foundation for understanding and potentially addressing retinal disorders.
PubMed: 38813437
DOI: 10.3389/fnmol.2024.1412407 -
Frontiers in Molecular Neuroscience 2024Dm9 neurons in have been proposed as functional homologs of horizontal cells in the outer retina of vertebrates. Here we combine genetic dissection of neuronal circuit...
Dm9 neurons in have been proposed as functional homologs of horizontal cells in the outer retina of vertebrates. Here we combine genetic dissection of neuronal circuit function, two-photon calcium imaging in Dm9 and inner photoreceptors, and immunohistochemical analysis to reveal novel insights into the functional role of Dm9 in early visual processing. Our experiments show that Dm9 receive input from all four types of inner photoreceptor R7p, R7y, R8p, and R8y. Histamine released from all types R7/R8 directly inhibits Dm9 via the histamine receptor Ort, and outweighs simultaneous histamine-independent excitation of Dm9 by UV-sensitive R7. Dm9 in turn provides inhibitory feedback to all R7/R8, which is sufficient for color-opponent processing in R7 but not R8. Color opponent processing in R8 requires additional synaptic inhibition by R7 of the same ommatidium via axo-axonal synapses and the second histamine receptor HisCl1. Notably, optogenetic inhibition of Dm9 prohibits color opponent processing in all types of R7/R8 and decreases intracellular calcium in photoreceptor terminals. The latter likely results from reduced release of excitatory glutamate from Dm9 and shifts overall photoreceptor sensitivity toward higher light intensities. In summary, our results underscore a key role of Dm9 in color opponent processing in and suggest a second role of Dm9 in regulating light adaptation in inner photoreceptors. These novel findings on Dm9 are indeed reminiscent of the versatile functions of horizontal cells in the vertebrate retina.
PubMed: 38813436
DOI: 10.3389/fnmol.2024.1347540 -
Proceedings. Biological Sciences May 2024The ambient daylight variation is coded by melanopsin photoreceptors and their luxotonic activity increases towards midday when colour temperatures are cooler, and...
The ambient daylight variation is coded by melanopsin photoreceptors and their luxotonic activity increases towards midday when colour temperatures are cooler, and irradiances are higher. Although melanopsin and cone photoresponses can be mediated via separate pathways, the connectivity of melanopsin cells across all levels of the retina enables them to modify cone signals. The downstream effects of melanopsin-cone interactions on human vision are however, incompletely understood. Here, we determined how the change in daytime melanopsin activation affects the human cone pathway signals in the visual cortex. A 5-primary silent-substitution method was developed to evaluate the dependence of cone-mediated signals on melanopsin activation by spectrally tuning the lights and stabilizing the rhodopsin activation under a constant cone photometric luminance. The retinal (white noise electroretinogram) and cortical responses (visual evoked potential) were simultaneously recorded with the photoreceptor-directed lights in 10 observers. By increasing the melanopsin activation, a reverse response pattern was observed with cone signals being supressed in the retina by 27% ( = 0.03) and subsequently amplified by 16% ( = 0.01) as they reach the cortex. We infer that melanopsin activity can amplify cone signals at sites distal to retinal bipolar cells to cause a decrease in the psychophysical Weber fraction for cone vision.
Topics: Humans; Rod Opsins; Retinal Cone Photoreceptor Cells; Visual Cortex; Adult; Electroretinography; Evoked Potentials, Visual; Female; Male; Young Adult; Photic Stimulation
PubMed: 38808443
DOI: 10.1098/rspb.2023.2708 -
Frontiers in Cell and Developmental... 2024Mitochondrial health has gained attention in a number of diseases, both as an indicator of disease state and as a potential therapeutic target. The quality and amount of...
BACKGROUND
Mitochondrial health has gained attention in a number of diseases, both as an indicator of disease state and as a potential therapeutic target. The quality and amount of mitochondrial DNA (mtDNA) and RNA (mtRNA) can be important indicators of mitochondrial and cell health, but are difficult to measure in complex tissues.
METHODS
mtDNA and mtRNA in zebrafish retina samples were fluorescently labeled using RNAscope™ hybridization, then mitochondria were stained using immunohistochemistry. Pretreatment with RNase was used for validation. Confocal images were collected and analyzed, and relative amounts of mtDNA and mtRNA were reported. Findings regarding mtDNA were confirmed using qPCR.
RESULTS
Signals from probes detecting mtDNA and mtRNA were localized to mitochondria, and were differentially sensitive to RNase. This labeling strategy allows for quantification of relative mtDNA and mtRNA levels in individual cells. As a demonstration of the method in a complex tissue, single photoreceptors in zebrafish retina were analyzed for mtDNA and mtRNA content. An increase in mtRNA but not mtDNA coincides with proliferation of mitochondria at night in cones. A similar trend was measured in rods.
DISCUSSION
Mitochondrial gene expression is an important component of cell adaptations to disease, stress, or aging. This method enables the study of mtDNA and mtRNA in single cells of an intact, complex tissue. The protocol presented here uses commercially-available tools, and is adaptable to a range of species and tissue types.
PubMed: 38808224
DOI: 10.3389/fcell.2024.1346778 -
Journal of Clinical Biochemistry and... May 2024Photoreceptor degeneration decreases light sensitivity and leads to vision loss and various retinal diseases. Neurotrophin-3, originating from Müller glial cells in the...
Photoreceptor degeneration decreases light sensitivity and leads to vision loss and various retinal diseases. Neurotrophin-3, originating from Müller glial cells in the retina, plays a key role in protecting photoreceptors from damage induced by light or hypoxia. This neuroprotective approach is important because there are no established methods to regenerate lost photoreceptors. Dietary supplements are one of the useful methods for improving eye health. () Jack, which is native to the tropical forest of Malaysia and other Southeast Asian countries, exhibits several medicinal properties. In the present study, we demonstrated that the water extract of roots enhanced neurotrophin-3 gene expression in primary rat Müller cells. Using a stepwise bioassay-guided fractionation and purification of root extracts, we isolated the active compound underlying neurotrophin-3 gene-enhancing activities. Mass spectrometry and nuclear magnetic resonance spectral data identified the compound as eurycomanone. This study provides evidence for the efficacy of and eurycomanone in enhancing neurotrophin-3 expression in Müller cells . Although the biological significance of this effect and its underlying mechanism remain to be elucidated, this study suggests that may be promising for improving eye health and must be further investigated.
PubMed: 38799139
DOI: 10.3164/jcbn.23-73 -
International Journal of Molecular... May 2024Greg Lemke's laboratory was one of the pioneers of research into the TAM family of receptor tyrosine kinases (RTKs). Not only was cloned in his laboratory, but his... (Review)
Review
Greg Lemke's laboratory was one of the pioneers of research into the TAM family of receptor tyrosine kinases (RTKs). Not only was cloned in his laboratory, but his group also extensively studied mice knocked out for individual or various combinations of the TAM RTKs , , and . Here we primarily focus on one of the paralogs-MERTK. We provide a historical perspective on rodent models of loss of function and their association with retinal degeneration and blindness. We describe later studies employing mouse genetics and the generation of newer knockout models that point out incongruencies with the inference that loss of MERTK-dependent phagocytosis is sufficient for severe, early-onset photoreceptor degeneration in mice. This discussion is meant to raise awareness with regards to the limitations of the original knockout mouse model generated using 129 derived embryonic stem cells and carrying 129 derived alleles and the role of these alleles in modifying knockout phenotypes or even displaying -independent phenotypes. We also suggest molecular approaches that can further Greg Lemke's scintillating legacy of dissecting the molecular functions of MERTK-a protein that has been described to function in phagocytosis as well as in the negative regulation of inflammation.
Topics: Animals; c-Mer Tyrosine Kinase; Phagocytosis; Mice, Knockout; Mice; Retinal Degeneration; Disease Models, Animal; Receptor Protein-Tyrosine Kinases; Humans; Inflammation
PubMed: 38791338
DOI: 10.3390/ijms25105299 -
Cell Death Discovery May 2024Damage to the ribosome or an imbalance in protein biosynthesis can lead to some human diseases, such as diabetic retinopathy (DR) and other eye diseases. Here, we...
Damage to the ribosome or an imbalance in protein biosynthesis can lead to some human diseases, such as diabetic retinopathy (DR) and other eye diseases. Here, we reported that the kri1l gene was responsible for retinal development. The kri1l gene encodes an essential component of the rRNA small subunit processome. The retinal structure was disrupted in kri1l mutants, which resulted in small eyes. The boundaries of each layer of cells in the retina were blurred, and each layer of cells was narrowed and decreased. The photoreceptor cells and Müller glia cells almost disappeared in kri1l mutants. The lack of photoreceptor cells caused a fear of light response. The development of the retina started without abnormalities, and the abnormalities began two days after fertilization. In the kri1l mutant, retinal cell differentiation was defective, resulting in the disappearance of cone cells and Müller cells. The proliferation of retinal cells was increased, while apoptosis was also enhanced in kri1l mutants. γ-H2AX upregulation indicated the accumulation of DNA damage, which resulted in cell cycle arrest and apoptosis. The kri1l mutation reduced the expression of some opsin genes and key retinal genes, which are also essential for retinal development.
PubMed: 38789412
DOI: 10.1038/s41420-024-02022-2 -
Gels (Basel, Switzerland) May 2024Tissue engineering is considered a promising approach to treating advanced degenerative maculopathies such as nonexudative age-related macular degeneration (AMD), the...
Tissue engineering is considered a promising approach to treating advanced degenerative maculopathies such as nonexudative age-related macular degeneration (AMD), the leading cause of blindness worldwide. The retina consists of several hierarchical tissue layers, each of which is supported by a layer underneath. Each of these layers has a different morphology and requires distinct conditions for proper assembly. In fact, a prerequisite step for the assembly of each of these layers is the organization of the layer underneath. Advanced retinal degeneration includes degeneration of the other retina layers, including the choroid, the retinal pigmented epithelium (RPE), and the photoreceptors. Here, we report a step-by-step fabrication process of a three-layer retina-like structure. The process included the 3D printing of a choroid-like structure in an extracellular matrix (ECM) hydrogel, followed by deposition of the RPE monolayer. After the formation of the blood vessel-RPE interface, the photoreceptor cells were deposited to interact with the RPE layer. At the end of the fabrication process, each layer was characterized for its morphology and expression of specific markers, and the integration of the three-layer retina was evaluated. We envision that such a retina-like structure may be able to attenuate the deterioration of a degenerated retina and improve engraftment and regeneration. This retinal implant may potentially be suitable for a spectrum of macular degenerative diseases for which there are currently no cures and may save millions from complete blindness.
PubMed: 38786253
DOI: 10.3390/gels10050336