Nature Communications (Apr 28, 2023)
A visual opsin from jellyfish enables precise temporal control of G protein signalling
van Wyk M, Kleinlogel S
This research focuses on understanding how the rhodopsin protein found in a box jellyfish utilizes a unique Gαs intracellular pathway to achieve fast vision. The study uncovers a mechanism where the rhodopsin protein constitutively binds to a single downstream Gαs partner, enabling rapid activation and inactivation of G-protein signaling within milliseconds. By studying the rhodopsin protein, van Wyk and Kleinlogel engineered an optogenetic tool and used it in viral gene therapy to restore light responses in blind mice.
More OptoDrum Publications
Journal of Neuroinflammation (May 22, 2023)
The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage
Zhu X, Liu W, Tang X, Chen Y, Ge X, Ke Q, Liang X, Gan Y, Zheng Y, Zou M, Deng M, Liu Y, Li DW, Gong L
DOI: 10.1186/s12974-023-02804-y >>
The cell death in retinal degenerative diseases, such as age-related macular degeneration (AMD) or
retinitis pigmentosa (RP), is often caused by the body’s own immune system, which attacks retinal cells. In this study, Zhu et al discuss the effects of a compound called dBET6 against retinal degeneration in response to light damage. dBET6 inhibits a molecular pathway of the innate immune system known as cGAS-STING. The research demonstrates that dBET6 treatment effectively prevents retinal degeneration and reduces inflammation in the retina caused by exposure to excessive light. The study suggests that dBET6 could potentially be used as a therapeutic agent to mitigate retinal degenerative conditions and offers insights into the underlying mechanisms involved in light-induced retinal damage.
Background: Chronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. We recently found the first-generation BET inhibitor JQ1 alleviated sodium iodate-induced retinal degeneration by suppressing cGAS-STING innate immunity. Here, we investigated the effects and mechanism of dBET6, a proteolysis‑targeting chimera (PROTAC) small molecule that selectively degrades BET by the ubiquitin‒proteasome system, in light-induced retinal degeneration.
Methods: Mice were exposed to bright light to induce retinal degeneration, and the activation of cGAS-STING was determined by RNA-sequencing and molecular biology. Retinal function, morphology, photoreceptor viability and retinal inflammation were examined in the presence and absence of dBET6 treatment.
Results: Intraperitoneal injection of dBET6 led to the rapid degradation of BET protein in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after light damage (LD). dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Analysis of single-cell RNA-sequencing results revealed cGAS-STING components were expressed in retinal microglia. LD led to dramatic activation of the cGAS-STING pathway, whereas dBET6 suppressed LD-induced STING expression in reactive macrophages/microglia and the related inflammatory response.
Conclusions: This study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration.
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- Vision Science>
Life Science Alliance (May 09, 2023)
Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage
Li S, Jakobs TC
DOI: 10.26508/lsa.202301976 >>
Li and Jacobs show that Vitamin C, administered through drinking water protects retinal ganglion cells during glaucoma and after optic nerve crush. The elucidate the pathway of Vitamin C action which involves reactive astrocytes. The positive effect of Vitamin C can be seen not only in histological examinations, but is also manifested in preserved visual acuity, as measured with Striatech’s OptoDrum.
Glaucoma is a common neurodegenerative disorder characterized by retinal ganglion cell death, astrocyte reactivity in the optic nerve, and vision loss. Currently, lowering the intraocular pressure (IOP) is the first-line treatment, but adjuvant neuroprotective approaches would be welcome. Vitamin C possesses neuroprotective activities that are thought to be related to its properties as a co-factor of enzymes and its antioxidant effects. Here, we show that vitamin C promotes a neuroprotective phenotype and increases gene expression related to neurotropic factors, phagocytosis, and mitochondrial ATP production. This effect is dependent on the up-regulation of secreted phosphoprotein 1 (SPP1) in reactive astrocytes via the transcription factor E2F1. SPP1+ astrocytes in turn promote retinal ganglion cell survival in a mouse model of glaucoma. In addition, oral administration of vitamin C lowers the IOP in mice. This study identifies an additional neuroprotective pathway for vitamin C and suggests a potential therapeutic role of vitamin C in neurodegenerative diseases such as glaucoma.
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- Optic Nerve Damage>
Brain Pathology (May 04, 2023)
Alleviating early demyelination in ischaemia/reperfusion by inhibiting sphingosine-1-phosphate receptor 2 could protect visual function from impairment
Xue J, Lin J, Liu Z, Zhang Q, Tang J, Han J, Wu S, Liu C, Zhao L, Li Y, Zhuo Y
DOI: 10.1111/bpa.13161 >>
Retinal ischemia/reperfusion (I/R) injury can cause permanent vision loss, and effective treatments are currently lacking. Xue et al have discovered that early damage to the optic nerve’s myelin sheath is a key factor in this injury. By targeting a receptor called S1PR2 and using a specific inhibitor called JTE-013, they were able to protect retinal cells, prevent demyelination, and promote visual function recovery.
Retinal ischaemia/reperfusion (I/R) injury is a common cause of retinal ganglion cell (RGC) apoptosis and axonal degeneration, resulting in irreversible visual impairment. However, there are no available neuroprotective and neurorestorative therapies for retinal I/R injury, and more effective therapeutic approaches are needed. The role of the myelin sheath of the optic nerve after retinal I/R remains unknown. Here, we report that demyelination of the optic nerve is an early pathological feature of retinal I/R and identify sphingosine-1-phosphate receptor 2 (S1PR2) as a therapeutic target for alleviating demyelination in a model of retinal I/R caused by rapid changes in intraocular pressure. Targeting the myelin sheath via S1PR2 protected RGCs and visual function. In our experiment, we observed early damage to the myelin sheath and persistent demyelination accompanied by S1PR2 overexpression after injury. Blockade of S1PR2 by the pharmacological inhibitor JTE-013 reversed demyelination, increased the number of oligodendrocytes, and inhibited microglial activation, contributing to the survival of RGCs and alleviating axonal damage. Finally, we evaluated the postoperative recovery of visual function by recording visual evoked potentials and assessing the quantitative optomotor response. In conclusion, this study is the first to reveal that alleviating demyelination by inhibiting S1PR2 overexpression may be a therapeutic strategy for retinal I/R-related visual impairment.
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- Retinal Ischemia-Reperfusion Injury·
- Vision Science>
Nature Communications (Apr 28, 2023)
A visual opsin from jellyfish enables precise temporal control of G protein signalling
van Wyk M, Kleinlogel S
DOI: 10.1038/s41467-023-38231-z >>
This research focuses on understanding how the rhodopsin protein found in a box jellyfish utilizes a unique Gαs intracellular pathway to achieve fast vision. The study uncovers a mechanism where the rhodopsin protein constitutively binds to a single downstream Gαs partner, enabling rapid activation and inactivation of G-protein signaling within milliseconds. By studying the rhodopsin protein, van Wyk and Kleinlogel engineered an optogenetic tool and used it in viral gene therapy to restore light responses in blind mice.
Phototransduction is mediated by distinct types of G protein cascades in different animal taxa: bilateral invertebrates typically utilise the Gαq pathway whereas vertebrates typically utilise the Gαt(i/o) pathway. By contrast, photoreceptors in jellyfish (Cnidaria) utilise the Gαs intracellular pathway, similar to olfactory transduction in mammals1. How this habitually slow pathway has adapted to support dynamic vision in jellyfish remains unknown. Here we study a light-sensing protein (rhodopsin) from the box jellyfish Carybdea rastonii and uncover a mechanism that dramatically speeds up phototransduction: an uninterrupted G protein-coupled receptor - G protein complex. Unlike known G protein-coupled receptors (GPCRs), this rhodopsin constitutively binds a single downstream Gαs partner to enable G-protein activation and inactivation within tens of milliseconds. We use this GPCR in a viral gene therapy to restore light responses in blind mice.
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- Applications:- 2 - 1
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- Vision Science>
iScience (Apr 19, 2023)
Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in PLP1 mutant mice
Abdelwahab T, Stadler D, Knöpper K, Arampatzi P, Saliba AE, Kastenmüller W, Martini R, Groh J
DOI: 10.1016/j.isci.2023.106698 >>
This study explores the role of CD8+ T cells in conditions where the myelin sheath is damaged. These T cells specifically target and attack mutated cells responsible for producing myelin, leading to nerve damage and degeneration. They found that early treatment with a specific medication can reduce the recruitment of harmful T cells and prevent further damage. However, targeting these T cells later on is less effective. Understanding these interactions may help develop new treatments for conditions involving myelin defects and inflammation.
Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct PLP1 mutations result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates T cell recruitment and neural damage, while later targeting of CNS-associated T cell populations is inefficient. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant myelinating oligodendrocytes. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.
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eNeuro (Apr 11, 2023)
Off Starburst Amacrine Cells in the Retina Trigger Looming-Evoked Fear Responses in Mice
Bohl JM, Gope J, Sharpe ZJ, Shehu A, Garrett A, Koehler CC, Hellmer CB, Ichinose T
DOI: 10.1523/ENEURO.0183-22.2023 >>
Looming dark stimuli (an expanding shadow) evoke evolutionary conserved fear or flight responses. This study looked at the effects on this behavior of ablating starburst amacrine cells, a specific interneuron in the retina which is involved in direction-selective retinal responses. Bohl et al found that looming-induced fear responses were eliminated when a sufficient number of OFF starburst cell were ablated. As a further behavioral readout to confirm successful starburst ablation, Bohl et al used measurements of the optomotor reflex which is known to depend on the direction-selective circuitry in the retina. OMR seemed to depend mostly on ON starburst cells, so that the two behavioral changes (OMR and looming-induced fear response) did not coincide in all mice.
A rapidly approaching dark object evokes an evolutionarily conserved fear response in both vertebrates and invertebrates, young to old. A looming visual stimulus mimics an approaching object and triggers a similarly robust fear response in mice, resulting in freeze and flight. However, the retinal neural pathway responsible for this innate response has not been fully understood. We first explored a variety of visual stimuli that reliably induced these innate responses, and found that a looming stimulus with 2-d acclimation consistently evoked fear responses. Because the fear responses were triggered by the looming stimulus with moving edges, but not by a screen flipping from light to dark, we targeted the starburst amacrine cells (SACs), crucial neurons for retinal motion detection. We used intraocular injection of diphtheria toxin (DT) in mutant mice expressing diphtheria toxin receptors (DTR) in SACs. The looming-evoked fear responses disappeared in half of the DT-injected mice, and the other mice still exhibited the fear responses. The optomotor responses (OMRs) were reduced or eliminated, which occurred independent of the disappearance of the fear responses. A histologic examination revealed that ON SACs were reduced in both mouse groups preserved or absent fear responses. In contrast, the number of OFF SACs was different among two groups. The OFF SACs were relatively preserved in mice exhibiting continued fear responses, whereas they were ablated in mice lacking fear response to looming stimulation. These results indicate that OFF SACs and the direction-selective pathway in the retina play a role in looming-induced fear behaviors.
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Frontiers in Drug Delivery (Mar 27, 2023)
CRISPR-mediated optogene expression from a cell-specific endogenous promoter in retinal ON-bipolar cells to restore vision
Maddalena A, Kleinlogel S
DOI: 10.3389/fddev.2023.934394 >>
Optogenetic restoration of visual function is a promising therapeutic avenue to restore vision after retinal degeneration. Targeted and efficient expression of optogenes, however, still proves challenging. In this study, Maddalena and Kleinlogel explored CRISPR-mediated expression of the optogene Opto-mGluR6 in retinal bipolar cells. They found, using Striatech’s OptoDrum, that treatment of otherwise blind rd1 mice improved their visual acuity significantly.
Retinitis pigmentosa, an inherited form of retinal degeneration, is characterized by a progressive loss of rods and subsequent degeneration of cones, leading to blindness. However, the remaining neural portion of the retina (bipolar and ganglion cells) remains anatomically and functionally intact for an extended time. A possible treatment to restore the light sensitivity of the retina consists of rendering the remaining retinal cells photosensitive using optogenetic tools like, for example, Opto-mGluR6, a light-sensitive mGluR6 receptor. We have previously demonstrated that AAV vector-mediated expression of Opto-mGluR6 in ON-bipolar cells restores visual function in otherwise blind mice. However, classical gene supplementation therapy still suffers from high off-target expression rates and uncontrollable target gene expression levels that may lead to either cytotoxicity or lack of functional restoration. To address these issues and achieve cell-specific and endogenously controlled Opto-mGluR6 expression, we employed the CRISPR/Cas technology—in particular, homology-independent targeted integration (HITI) and microhomology-dependent targeted integration (MITI)—to knock-in the Opto-mGluR6 gene behind the ON-bipolar cell-specific GRM6 promoter. We compared four Cas systems in vitro and show that SpCas9 for HITI and LbCpf1 for MITI are well suited to promoting knock-in. As AAV2-mediated ON-bipolar cell transduction resulted in inefficiency, we evaluated Exo-AAVs as delivery vehicles and found Exo-AAV1 efficient for targeting ON-bipolar cells. We demonstrate that intravitreal injection of Exo-AAV1 carrying vectors that promote MITI significantly improved visual acuity in otherwise blind rd1 mice. We conclude by confirming and providing a qualitative evaluation of the MITI-mediated knock-in in the correct genomic locus.
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- Retinal Degeneration·
- Vision Science>
Cell Reports (Mar 03, 2023)
Postsynaptic neuronal activity promotes regeneration of retinal axons
Varadarajan SG, Wang F, Dhande OS, Le P, Duan X, Huberman AD
DOI: 10.1016/j.celrep.2023.112476 >>
Journal Club
Varadarajan et al have discovered that stimulating specific brain cells can promote the regeneration of damaged optic nerve fibers, potentially restoring lost vision. By increasing neural activity in the brain’s visual target neurons, they found that retinal ganglion cell (RGC) axons can regrow and reconnect with their proper synaptic targets. This finding highlights the importance of postsynaptic brain targets in repairing visual circuits and offers hope for developing strategies to restore vision in individuals with vision loss.
The wiring of visual circuits requires that retinal neurons functionally connect to specific brain targets, a process that involves activity-dependent signaling between retinal axons and their postsynaptic targets. Vision loss in various ophthalmological and neurological diseases is caused by damage to the connections from the eye to the brain. How postsynaptic brain targets influence retinal ganglion cell (RGC) axon regeneration and functional reconnection with the brain targets remains poorly understood. Here, we established a paradigm in which the enhancement of neural activity in the distal optic pathway, where the postsynaptic visual target neurons reside, promotes RGC axon regeneration and target reinnervation and leads to the rescue of optomotor function. Furthermore, selective activation of retinorecipient neuron subsets is sufficient to promote RGC axon regeneration. Our findings reveal a key role for postsynaptic neuronal activity in the repair of neural circuits and highlight the potential to restore damaged sensory inputs via proper brain stimulation.
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- Vision Science>
Neuron (Jan 04, 2023)
CyclinD2-mediated regulation of neurogenic output from the retinal ciliary margin is perturbed in albinism
Slavi N, Balasubramanian R, Lee MA, Liapin M, Oaks-Leaf R, Peregrin J, Potenski A, Troy CM, Ross ME, Herrera E, Kos-midis S, John SWM, Mason CA
DOI: 10.1016/j.neuron.2022.10.025 >>
This article is an in-depth investigation of molecular alterations underlying chiasmatic misrouting in the albino binocular circuit. During development, in a specialized retinal niche—the ciliary margin—fewer cells express the cellcycle regulator CyclinD2. Consequently, the cell cycle is elongated, resulting in fewer ipsilaterally projecting RGCs and perturbed binocular vision.
In albinism, aberrations in the ipsi-/contralateral retinal ganglion cell (RGC) ratio compromise the functional integrity of the binocular circuit. Here, we focus on the mouse ciliary margin zone (CMZ), a neurogenic niche at the embryonic peripheral retina, to investigate developmental processes regulating RGC neurogenesis and identity acquisition. We found that the mouse ventral CMZ generates predominantly ipsilaterally projecting RGCs, but this output is altered in the albino visual system because of CyclinD2 downregulation and disturbed timing of the cell cycle. Consequently, albino as well as CyclinD2-deficient pigmented mice exhibit diminished ipsilateral retinogeniculate projection and poor depth perception. In albino mice, pharmacological stimulation of calcium channels, known to upregulate CyclinD2 in other cell types, augmented CyclinD2-dependent neurogenesis of ipsilateral RGCs and improved stereopsis. Together, these results implicate CMZ neurogenesis and its regulators as critical for the formation and function of the mammalian binocular circuit.
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Cell Death & Disease (Nov 08, 2022)
Neurovascular injury associated non-apoptotic endothelial caspase-9 and astroglial caspase-9 mediate inflammation and contrast sensitivity decline
Colón Ortiz C, Neal AM, Avrutsky MI, Choi M, Smart J, Lawson J, Troy CM
DOI: 10.1038/s41419-022-05387-3 >>
Journal Club
Neurovascular injury, such as retinal vein occlusion, triggers expression of endothelial caspase-9 (EC Casp9). EC Casp9 induces pathological changes, including retinal edema, capillary ischemia, and neurodegeneration. One of the behavioral consequences is decline of contrast sensitivity, as shown with our OptoDrum. This paper gives new mechanistic insights into EC Casp9 action.
Retinal neurovascular injuries are a leading cause of vision loss in young adults presenting unmet therapeutic needs. Neurovascular injuries damage homeostatic communication between endothelial, pericyte, glial, and neuronal cells through signaling pathways that remain to be established. To understand the mechanisms that contribute to neuronal death, we use a mouse model of retinal vein occlusion (RVO). Using this model, we previously discovered that after vascular damage, there was non-apoptotic activation of endothelial caspase-9 (EC Casp9); knock-out of EC Casp9 led to a decrease in retinal edema, capillary ischemia, and neuronal death. In this study, we aimed to explore the role of EC Casp9 in vision loss and inflammation. We found that EC Casp9 is implicated in contrast sensitivity decline, induction of inflammatory cytokines, and glial reactivity. One of the noted glial changes was increased levels of astroglial cl-caspase-6, which we found to be activated cell intrinsically by astroglial caspase-9 (Astro Casp9). Lastly, we discovered that Astro Casp9 contributes to capillary ischemia and contrast sensitivity decline after RVO (P-RVO). These findings reveal specific endothelial and astroglial non-apoptotic caspase-9 roles in inflammation and neurovascular injury respectively; and concomitant relevancy to contrast sensitivity decline.
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- Neurovascular Injury>
Communications Biology (Oct 20, 2022)
Bipolar cell targeted optogenetic gene therapy restores parallel retinal signaling and high-level vision in the degenerated retina
Kralik J, van Wyk M, Stocker N, Kleinlogel S
DOI: 10.1038/s42003-022-04016-1 >>
Kralik et al show successful optogenetic vision restoration in blind mice by expressing an engineered melanopsin-mGluR6 chimeric protein in ON bipolar cells. The treated mice show visual behavior that approaches the quality of wild type mice, shown with optomotor measurements. The responses of retinal ganglion cells are highly diverse, indicating that parallel processing is restored in treated retinas.
Optogenetic gene therapies to restore vision are in clinical trials. Whilst current clinical approaches target the ganglion cells, the output neurons of the retina, new molecular tools enable efficient targeting of the first order retinal interneurons, the bipolar cells, with the potential to restore a higher quality of vision. Here we investigate retinal signaling and behavioral vision in blind mice treated with bipolar cell targeted optogenetic gene therapies. All tested tools, including medium-wave opsin, Opto-mGluR6, and two new melanopsin based chimeras restored visual acuity and contrast sensitivity. The best performing opsin was a melanopsin-mGluR6 chimera, which in some cases restored visual acuities and contrast sensitivities that match wild-type animals. Light responses from the ganglion cells were robust with diverse receptive-field types, inferring elaborate inner retinal signaling. Our results highlight the potential of bipolar cell targeted optogenetics to recover high-level vision in human patients with end-stage retinal degenerations.
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- OptoDrum/
- Applications:- 1 - 1
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Molecular Metabolism (Oct 18, 2022)
Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome
Maity-Kumar G, Ständer L, DeAngelis M, Lee S, Molenaar A, Becker L, Garrett L, Amerie OV, Hoelter SM, Wurst W, Fuchs H, Feuchtinger A, Gailus-Durner V, Garcia-Caceres C, Othman AE, Brockmann C, Schöffling VI, Beiser K, Krude H, Mroz PA, Hofmann S, Tuckermann J, DiMarchi RD, Hrabe de Angelis M, Tschöp MH, Pfluger PT, Müller TD
DOI: 10.1016/j.molmet.2022.101616 >>
Maity-Kumar et al provide extensive characterization of a new mouse model for the Allan-Herndon-Dudley syn-drome (AHDS).
Objective: The Allan-Herndon-Dudley syndrome (AHDS) is a severe disease caused by dysfunctional central thyroid hormone transport due to functional loss of the monocarboxylate transporter 8 (MCT8). In this study, we assessed whether mice with concomitant deletion of the thyroid hormone transporters Mct8 and the organic anion transporting polypeptide (Oatp1c1) represent a valid preclinical model organism for the AHDS.
Methods: We generated and metabolically characterized a new CRISPR/Cas9 generated Mct8/Oatp1c1 double-knockout (dKO) mouse line for the clinical features observed in patients with AHDS.
Results: We show that Mct8/Oatp1c1 dKO mice mimic key hallmarks of the AHDS, including decreased life expectancy, central hypothyroidism, peripheral hyperthyroidism, impaired neuronal myelination, impaired motor abilities and enhanced peripheral thyroid hormone action in the liver, adipose tissue, skeletal muscle and bone.
Conclusions: We conclude that Mct8/Oatp1c1 dKO mice are a valuable model organism for the preclinical evaluation of drugs designed to treat the AHDS.
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- OptoDrum/
- Applications:- 2 - 1
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- Rare Disease>
Biomolecules (Oct 07, 2022)
Targeting Cholesterol Homeostasis Improves Recovery in Experimental Optic Neuritis
Godwin CR, Anders JJ, Cheng L, Elwood BW, Kardon RH, Gramlich OW
DOI: 10.3390/biom12101437 >>
Chronic autoimmune diseases, such as multiple sclerosis (MS), lead to demyelination of neurons. Recovery after demyelinating events is limited by cholesterol recycling. Godwin et al show that gentasic acid (GA) treatment amelio-rates the damages in a murine model of optic nerve demyelination, MOG-induced experimental autoimmune encephalomyelitis (EAE). Improved cholesterol homeostasis may therefore contribute to rehabilitation of MS patients.
Acute optic neuritis (ON) is a common cause of vision loss and is often associated with multiple sclerosis (MS). Cholesterol recycling has been identified as a key limiting factor in recovery after demyelination events. Thus, the purpose of our study was to determine if the augmentation of cholesterol transport by gentisic acid (GA) benefits retinal ganglion cell (RGC) development and myelination in organoid systems and enables the recovery of the ocular phenotype upon systemic GA treatment in a MOG-induced experimental autoimmune encephalomyelitis (EAE) ON model. The retinal organoids treated with GA demonstrate an accelerated maturation when compared to the conventionally derived organoids, which was evidenced by the improved organization of Brn3a-GFP+RGC and increased synaptogenesis. A GA supplementation in brain organoids leads to a 10-fold increase in NG2 and Olig2 expression. Weekly GA injections of EAE mice significantly lessened motor-sensory impairment, protected amplitudes in pattern electroretinogram recordings, and preserved visual acuity over the study period of 56 days. Furthermore, GA-treated EAE mice revealed diminished GCL/IPL complex thinning when compared to the untreated EAE mice. An optic nerve histopathology revealed less severe grades of demyelination in the GA-treated EAE cohort and fewer infiltrating cells were observed. Interventions to improve cholesterol homeostasis may be a viable approach to promoting the rehabilitation of MS patients.
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- OptoDrum/
- Applications:- 2 - 1
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- Optic Neuritis>
Experimental Eye Research (Oct 06, 2022)
Immune responses in mice after blast-mediated traumatic brain injury TBI autonomously contribute to retinal ganglion cell dysfunction and death
Harper MM, Gramlich OW, Elwood BW, Boehme NA, Dutca LM, Kuehn MH
DOI: 10.1016/j.exer.2022.109272 >>
Blast injuries are common in modern warfare. They lead to immediate damage to the nervous system, but often develop into chronic disease with progressive deterioration, including in the visual system. It is proposed that neuroinflammatory processes underly this chronic phase. 4 weeks after injury, Harper et al transferred splenocytes of mice exposed to blast-mediated traumatic brain injury (bTBI) into naïve animals. Those naïve animals developed visual symptoms and experienced ganglion cell dysfunction similar to the blast-injured mice, suggesting that the immune system is indeed involved in the chronic phase of bTBI.
Purpose: The purpose of this study was to examine the role of the immune system and its influence on chronic retinal ganglion cell (RGC) dysfunction following blast-mediated traumatic brain injury (bTBI).
Methods: C57BL/6J and B6.129S7-Rag1tm1Mom/J (Rag-/-) mice were exposed to one blast injury of 140 kPa. A separate cohort of C57BL/6J mice was exposed to sham-blast. Four weeks following bTBI mice were euthanized, and splenocytes were collected. Adoptive transfer (AT) of splenocytes into naïve C57BL/6J recipient mice was accomplished via tail vein injection. Three groups of mice were analyzed: those receiving AT of splenocytes from C57BL/6J mice exposed to blast (AT-TBI), those receiving AT of splenocytes from C57BL/6J mice exposed to sham (AT-Sham), and those receiving AT of splenocytes from Rag-/- mice exposed to blast (AT-Rag-/-). The visual function of recipient mice was analyzed with the pattern electroretinogram (PERG), and the optomotor response (OMR). The structure of the retina was evaluated using optical coherence tomography (OCT), and histologically using BRN3A-antibody staining.
Results: Analysis of the PERG showed a decreased amplitude two months post-AT that persisted for the duration of the study in AT-TBI mice. We also observed a significant decrease in the retinal thickness of AT-TBI mice two months post-AT compared to sham, but not at four or six months post-AT. The OMR response was significantly decreased in AT-TBI mice 5- and 6-months post-AT. BRN3A staining showed a loss of RGCs in AT-TBI and AT-Rag-/- mice.
Conclusion: These results suggest that the immune system contributes to chronic RGC dysfunction following bTBI.
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- Applications:- 1 - 1
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Journal of Medicinal Chemistry (Sep 08, 2022)
Identification of Nitric Oxide-Donating Ripasudil Derivatives with Intraocular Pressure Lowering and Retinal Ganglion Cell Protection Activities
Yang Z, Wu J, Wu K, Luo J, Li C, Zhang J, Zhao M, Mei T, Liu X, Shang B, Zhang Y, Zhao L, Huang Z
DOI: 10.1021/acs.jmedchem.2c00600 >>
Ripasudil (trade name Glanatec) is a rho kinase inhibitor drug used for the treatment of glaucoma and ocular hypertension. Yang et al tested 6 new derivatives of ripasudil in chronic ocular hypertension glaucoma mice, and found that one of them, RNO-6, showed superior efficacy compared to ripasudil.
Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a new group of NO-donating ripasudil derivatives RNO-1-RNO-6 was designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound RNO-6 maintained potent ROCK inhibitory and NO releasing abilities, reversibly depolymerized F-actin, and suppressed mitochondrial respiration in human trabecular meshwork (HTM) cells. Topical administration of RNO-6 (0.26%) in chronic ocular hypertension glaucoma mice exhibited significant IOP lowering and visual function and retinal ganglion cell (RGC) protection activities, superior to an equal molar dose of ripasudil. RNO-6 could be a promising agent for glaucoma or ocular hypertension, warranting further investigation.
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- OptoDrum/
- Applications:- 1 - 1
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Biomaterials Science (Aug 24, 2022)
In situ-crosslinked hydrogel-induced experimental glaucoma model with persistent ocular hypertension and neurodegeneration
Lin J, Xue J, Xu Q, Liu Z, Zhao C, Tang J, Han J, A S, Wang W, Zhuo Y, Li Y
DOI: 10.1039/d2bm00552b >>
Lin et al present a new experimental animal model for glaucoma. By injecting a newly formulated hydrogel, they induce consistent intraocular pressure increase.
A reliable animal model providing chronic and persistent ocular hypertension and characteristic neurodegeneration is essential to recapitulate human glaucoma and understand the underlying pathophysiological mechanisms behind this disease. Many approaches have been tried to establish persistently elevated intraocular pressure (IOP), while no efficient model and no systematic evaluation has been widely accepted yet. Herein, we developed a novel approach to reliably induce persistent IOP elevation using an injectable hydrogel formulated by hyperbranched macromolecular poly(ethylene glycol) (HB-PEG) and thiolated hyaluronic acid (HA-SH) under physiological conditions and established a systematic system for model evaluation. By formulation screening, an appropriate hydrogel with proper mechanical property, non-swelling profile and cytocompatibility was selected for further experiment. By intracameral injection, a persistent IOP elevation over 50% above baseline was obtained and it led to progressive retinal ganglion cell loss and ganglion cell complex thickness reduction. The evaluation of the efficacy of the model was thoroughly analyzed by whole-mounts retina immunostaining, optical coherence tomography, and hematoxylin-eosin staining for histological changes and by electroretinography for visual function changes. The N35-P50 amplitude of the pattern electroretinography and the N2-P2 amplitude of the flash visual-evoked potential were decreased, while the scotopic electroretinography showed no statistically significant changes. The in situ-forming HB-PEG/HA-SH hydrogel system could be an appropriate strategy for developing a reliable experimental glaucoma model without any confounding factors. We expect this model would be conducive to the development of neuroprotective and neuro-regenerative therapies.
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- OptoDrum/
- Applications:- 2 - 1
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- Retinal Degeneration>
Translational Vision Science & Technology (Aug 01, 2022)
Noninvasive Ophthalmic Imaging Measures Retinal Degeneration and Vision Deficits in Ndufs4−/− Mouse Model of Mitochondrial Complex I Deficiency
Avrutsky MI, Lawson JM, Smart JE, Chen CW, Troy CM
DOI: 10.1167/tvst.11.8.5 >>
Mitochondrial complex I disorders are a heterogeneous group of rare inherited diseases caused by mutations affecting proteins in the mitochondrial electron transport chain. Neurological and ophthalmic pathologies are common to many forms of complex I deficiency, due to the high energy demands of central nervous system tissues. Avrutsky et al characterized one such mouse model, carrying a mutation in Ndufs4 (NADH:ubiquinone oxidoreductase Fe-S pro-tein 4), which shows fast retinal degeneration within only a few weeks. They show that a range of non-invasive techniques (OCT for structural changes, ERG for electrophysiological properties, and OMR with our OptoDrum for behavioral assessment) can capture relevant measures of disease progression.
Purpose: To characterize postnatal ocular pathology in a Ndufs4−/− mouse model of complex I deficiency using noninvasive retinal imaging and visual testing.
Methods: Ndufs4−/− mice and wild-type (WT) littermates were analyzed at 3, 5, and 7 weeks postnatal. Retinal morphology was visualized by optical coherence tomography (OCT). OCT images were analyzed for changes in retinal thickness and reflectivity profiles. Visual function was assessed by electroretinogram (ERG) and optomotor reflex (OMR).
Results: Ndufs4−/− animals have normal OCT morphology at weaning and develop inner plexiform layer atrophy over weeks 5 to 7. Outer retinal layers show hyporeflectivity of the external limiting membrane (ELM) and photoreceptor ellipsoid zone (EZ). Retinal function is impaired at 3 weeks, with profound deficits in b-wave, a-wave, and oscillatory potential amplitudes. The b-wave and oscillatory potential implicit times are delayed, but the a-wave implicit time is unaffected. Ndufs4−/− animals have normal OMR at 3 weeks and present with increasing acuity and contrast OMR deficits at 5 and 7 weeks. Physiological thinning of inner retinal layers, attenuation of ELM reflectivity, and attenuation of ERG b- and a-wave amplitudes occur in WT C57BL/6 littermates between weeks 3 and 7.
Conclusions: Noninvasive ocular imaging captures early-onset retinal degeneration in Ndufs4−/− mice and is a tractable approach for investigating retinal pathology subsequent to complex I deficiency.
Translational relevance: Ophthalmic imaging captures clinically relevant measures of retinal disease in a fast-progressing mouse model of complex I deficiency consistent with human Leigh syndrome.
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- Applications:- 3 - 1
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- Retinal Degeneration·
- Vision Science>
Annals Of Rheumatic Diseases (Jul 22, 2022)
Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome
Kozycki CT, Kodati S, Huryn L, Wang H, Warner BM, Jani P, Hammoud D, Abu-Asab MS, Jittayasothorn Y, Mattapallil MJ, Tsai WL, Ullah E, Zhou P, Tian X, Soldatos A, Moutsopoulos N, Kao-Hsieh M, Heller T, Cowen EW, Lee CR, Toro C, Kalsi S, Khavandgar Z, Baer A, Beach M, Long Priel D, Nehrebecky M, Rosenzweig S, Romeo T, Deuitch N, Brenchley L, Pelayo E, Zein W, Sen N, Yang AH, Farley G, Sweetser DA, Briere L, Yang J, de Oliveira Poswar F, Schwartz IVD, Silva Alves T, Dusser P, Koné-Paut I, Touitou I, Titah SM, van Hagen PM, van Wijck RTA, van der Spek PJ, Yano H, Benneche A, Apalset EM, Jansson RW, Caspi RR, Kuhns DB, Gadina M, Takada H, Ida H, Nishikomori R, Verrecchia E, Sangiorgi E, Manna R, Brooks BP, Sobrin L, Hufnagel RB, Beck D, Shao F, Ombrello AK, Aksentijevich I, Kastner DL; Undiagnosed Diseases Network
DOI: 10.1136/annrheumdis-2022-222629 >>
In a large study, spanning identification of patient cohorts, characterization of those patients’ phenotypes, genetic analysis, generation and characterization of animal models, Kozycki et al show that ROSAH syndrome (cause by mutations in the ALPK1 gene) is an autoinflammatory disease with a large range of consequences. They show that treatment with anti-inflammatory drugs is successful. The newly generated animal model only partially replicated the human phenotypes. For example, the mice did not have visual deficits and showed no signs of retinal degeneration.
Objectives: To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease.
Methods: This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling.
Results: The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow.
Conclusion: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.
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- Retinal Dystrophy>
Frontiers in Cellular Neuroscience (Jul 19, 2022)
Stage-Dependent Changes of Visual Function and Electrical Response of the Retina in the rd10 Mouse Model
Cha S, Ahn J, Jeong Y, Lee YH, Kim HK, Lee D, Yoo Y, Goo YS
DOI: 10.3389/fncel.2022.926096 >>
Cha et al characterize the rd10 mouse model at the level of behavior (optomotor reflex with our OptoDrum), as well as ex-vivo spike recordings of ganglion cells to light stimulation and electrical stimulation. Thy find that the retina responds differently to electrical stimulation depending on the stage of degeneration.
One of the critical prerequisites for the successful development of retinal prostheses is understanding the physio-logical features of retinal ganglion cells (RGCs) in the different stages of retinal degeneration (RD). This study used our custom-made rd10 mice, C57BL/6-Pde6bem1(R560C)Dkl/Korl mutated on the Pde6b gene in C57BL/6J mouse with the CRISPR/Cas9-based gene-editing method. We selected the postnatal day (P) 45, P70, P140, and P238 as representa-tive ages for RD stages. The optomotor response measured the visual acuity across degeneration stages. At P45, the rd10 mice exhibited lower visual acuity than wild-type (WT) mice. At P140 and older, no optomotor response was observed. We classified RGC responses to the flashed light into ON, OFF, and ON/OFF RGCs via in vitro multichannel recording. With degeneration, the number of RGCs responding to the light stimulation decreased in all three types of RGCs. The OFF response disappeared faster than the ON response with older postnatal ages. We elicited RGC spikes with electrical stimulation and analyzed the network-mediated RGC response in the rd10 mice. Across all postnatal ages, the spikes of rd10 RGCs were less elicited by pulse amplitude modulation than in WT RGCs. The ratio of RGCs showing multiple peaks of spike burst increased in older ages. The electrically evoked RGC spikes by the pulse amplitude modulation differ across postnatal ages. Therefore, degeneration stage-dependent stimulation strategies should be considered for developing retinal prosthesis and successful vision restoration.
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- Applications:- 4 - 1
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- Rare Disease·
- Retinal Degeneration·
- Vision Science>
Biomaterials (May 01, 2022)
TNF-α stimulation enhances the neuroprotective effects of gingival MSCs derived exosomes in retinal ischemia-reperfusion injury via the MEG3/miR-21a-5p axis
Yu Z, Wen Y, Jiang N, Li Z, Guan J, Zhang Y, Deng C, Zhao L, Zheng SG, Zhu Y, Su W, Zhuo Y
DOI: 10.1016/j.biomaterials.2022.121484 >>
Exosomes are small vesicles enclosed by a single outer membrane secreted from cells, ranging from 30 to 200 nm in diameter, containing messenger RNAs, non-coding RNAs, proteins, and biological factors, and they may play a cru-cial role in intercellular communication. Exosomes have been identified as potential therapeutic methods and drug delivery tools. Exosomes derived from mesenchymal stem cells (MSCs) have been investigated in disorders such as stroke, corneal diseases, and liver diseases, but not yet in an acute glaucoma model, such as the ischemia-reperfusion model in the eye. Yu et al show that exosomes from MSCs have strong neuroprotective effects which is even better when the MSCs had been stimulated with TNF-α, and they identify the underlying signaling pathway. Their findings my pave the way for a new cell-free therapeutic approach for glaucoma.
Retinal ischemia-reperfusion injury (IRI) is one of the main pathogenic mechanisms of glaucoma, which are largely unknown, including neuroinflammation and neuronal death in the pathological process. In our previous studies, mesenchymal stem cells (MSCs) have been reported to play anti-inflammatory and neuroprotective roles. Addition-ally, conditioned culture medium (CM) of MSCs stimulated by TNF-α have achieved better antiallergic effects in an experimental allergic conjunctivitis mouse model. However, there is an urgent need for cell-free therapy approach-es, like exosomes, to reduce the side effects of autoimmunity. The present study aimed to elucidate the pathways involving TNF-α-stimulated gingival MSC (GMSC)-exosomes (TG-exos), in modulating inflammatory microglia and alleviating apoptosis. In this study, exosomes from the CM of GMSCs were isolated by ultracentrifugation and were injected into the vitreous of mice. The results showed that intraocular injection of TG-exos into mice with IRI nota-bly reduced inflammation and cell loss than that with G-exos (GMSC-exosomes). Similar results were observed in vitro. Additionally, with the microRNA (miR) arrays, it was found that miR-21-5p acted as a crucial factor in TG-exos for neuroprotection and anti-inflammation. Following target prediction and dual-luciferase assay suggested that miR-21-5p played a role by combining with programmed cell death 4 (PDCD4), which was regulated by the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) as a competing endogenous RNA (ceRNA). This study demonstrates a new therapeutic pathway for neuroprotection against IRI by delivering miR-21-5p-enriched exosomes through MEG3/miR-21-5p/PDCD4 axis and paves the way for the establishment of a cell-free therapeutic approach for glaucoma.
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Frontiers in Pharmacology (Mar 21, 2022)
Chronic Proinflammatory Signaling Accelerates the Rate of Degeneration in a Spontaneous Polygenic Model of Inherited Retinal Dystrophy
Hollingsworth TJ, Wang X, White WA, Simpson RN, Jablonski MM
DOI: 10.3389/fphar.2022.839424 >>
Journal Club
Hollingsworth et al describe and characterize a new polygenic mouse model of inherited retinal dystrophies, the BXD32 mouse strain. They present evidence that a proinflammatory environment in the retina supports and accelerates the degeneration of the retina and the loss of visual function.
Collectively, retinal neurodegenerative diseases are comprised of numerous subtypes of disorders which result in loss of a varying cell types in the retina. These diseases can range from glaucoma, which results in retinal ganglion cell death, to age-related macular degeneration and retinitis pigmentosa, which result in cell death of the retinal pigment epithelium, photoreceptors, or both. Regardless of the disease, it's been recently found that increased release of proinflammatory cytokines and proliferation of active microglia result in a remarkably proinflammatory microenvironment that assists in the pathogenesis of the disease; however, many of the details of these inflammatory events have yet to be elucidated. In an ongoing study, we have used systems genetics to identify possible models of spontaneous polygenic age-related macular degeneration by mining the BXD family of mice using single nucleotide polymorphism analyses of known genes associated with the human retinal disease. One BXD strain (BXD32) was removed from the study as the rate of degeneration observed in these animals was markedly increased with a resultant loss of most all photoreceptors by 6 months of age. Using functional and anatomical exams including optokinetic nystamography, funduscopy, fluorescein angiography, and optical coherence tomography, along with immunohistochemical analyses, we show that the BXD32 mouse strain exhibits a severe neurodegenerative phenotype accompanied by adverse effects on the retinal vasculature. We also expose the concurrent establishment of a chronic proinflammatory microenvironment including the TNFα secretion and activation of the NF-κB and JAK/STAT pathways with an associated increase in activated macrophages and phagoptosis. We conclude that the induced neuronal death and proinflammatory pathways work synergistically in the disease pathogenesis to enhance the rate of degeneration in this spontaneous polygenic model of inherited retinal dystrophy.
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Journal of Neuroinflammation (Feb 23, 2022)
B cell-dependent EAE induces visual deficits in the mouse with similarities to human autoimmune demyelinating diseases
Joly S, Mdzomba JB, Rodriguez L, Morin F, Vallières L, Pernet V
DOI: 10.1186/s12974-022-02416-y >>
The experimental autoimmune encephalomyelitis (EAE) mouse model is commonly used to study visual impairments associated with autoimmune demyelinating diseases. EAE is classically induced by immunization with the peptide MOG35-55. This mouse model lacks certain characteristics of analog diseases in humans, in particular the participation of B-cells in the immune response. Joly et al characterize the effects of immunization with a different peptide, bMOG, and find that these mice show hallmarks of common human diseases, such as multiple sclerosis and neuromyelitis optica. This new mouse model therefore offers new avenues to test protective or restorative ophthalmic treatments.
Background: In the field of autoimmune demyelinating diseases, visual impairments have extensively been studied using the experimental autoimmune encephalomyelitis (EAE) mouse model, which is classically induced by immun-ization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). However, this model does not involve B cells like its human analogs. New antigens have thus been developed to induce a B cell-dependent form of EAE that bet-ter mimics human diseases. Methods: The present study aimed to characterize the visual symptoms of EAE induced with such an antigen called bMOG. After the induction of EAE with bMOG in C57BL/6J mice, visual function chang-es were studied by electroretinography and optomotor acuity tests. Motor deficits were assessed in parallel with a standard clinical scoring method. Histological examinations and Western blot analyses allowed to follow retinal neuron survival, gliosis, microglia activation, opsin photopigment expression in photoreceptors and optic nerve demyelination. Disease effects on retinal gene expression were established by RNA sequencing. Results: We ob-served that bMOG EAE mice exhibited persistent loss of visual acuity, despite partial recovery of electroretinogram and motor functions. This loss was likely due to retinal inflammation, gliosis and synaptic impairments, as evi-denced by histological and transcriptomic data. Further analysis suggests that the M-cone photoreceptor pathway was also affected. Conclusion: Therefore, by documenting visual changes induced by bMOG and showing similari-ties to those seen in diseases such as multiple sclerosis and neuromyelitis optica, this study offers a new approach to test protective or restorative ophthalmic treatments.
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Biomolecules (Feb 09, 2022)
Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models
Zeng H, Dumitrescu AV, Wadkins D, Elwood BW, Gramlich OW, Kuehn MH
DOI: 10.3390/biom12020281 >>
In two mouse models of Glaucoma, Zeng et al show that Pioglitazone, given orally, can reduce or even reverse vision loss. Pioglitazone reduces inflammatory responses. The positive effects could be observed even with continued elevation of intraocular pressure, suggesting that the neuroinflammation experienced during Glaucoma may be more harmful than the elevated pressure.
Neuroinflammation significantly contributes to the pathophysiology of several neurodegenerative diseases. This is also the case in glaucoma and may be a reason why many patients suffer from progressive vision loss despite max-imal reduction in intraocular pressure. Pioglitazone is an agonist of the peroxisome proliferator-activated receptor gamma (PPARγ) whose pleiotrophic activities include modulation of cellular energy metabolism and reduction in inflammation. In this study we employed the DBA2/J mouse model of glaucoma with chronically elevated intraocu-lar pressure to investigate whether oral low-dose pioglitazone treatment preserves retinal ganglion cell (RGC) sur-vival. We then used an inducible glaucoma model in C57BL/6J mice to determine visual function, pattern electro-retinographs, and tracking of optokinetic reflex. Our findings demonstrate that pioglitazone treatment does signifi-cantly protect RGCs and prevents axonal degeneration in the glaucomatous retina. Furthermore, treatment pre-serves and partially reverses vision loss in spite of continuously elevated intraocular pressure. These data suggest that pioglitazone may provide treatment benefits for those glaucoma patients experiencing continued vision loss.
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Neurology: Neuroimmunology & Neuroinflammation (Jan 13, 2022)
Antineonatal Fc Receptor Antibody Treatment Ameliorates MOG-IgG-Associated Experimental Autoimmune En-cephalomyelitis
Remlinger J, Madarasz A, Guse K, Hoepner R, Bagnoud M, Meli I, Feil M, Abegg M, Linington C, Shock A, Boroojerdi B, Kiessling P, Smith B, Enzmann V, Chan A, Salmen A
DOI: 10.1212/NXI.0000000000001134 >>
Journal Club
Demyelinating autoimmune diseases usually impact the optic nerve and thus visual abilities. Optomotor reflex measurements can therefore be used to non-invasively monitor disease progression and treatment efficacy. Remlinger et al studied MOGAD, a rare autoimmune demyelinating CNS disorder, in a murine model of experimental autoimmune encephalomyelitis (EAE). They assessed the effects of treating those mice with monoclonal antibodies against the neonatal Fc receptor and found that this treatment reduced the severity of the disease. Measurements of visual acuity with Striatech’s OptoDrum correlated well with other disease markers.
Background and Objectives Myelin oligodendrocyte glycoprotein antibody–associated disorder (MOGAD) is a rare, autoimmune demyelinating CNS disorder, distinct from multiple sclerosis and neuromyelitis optica spectrum disor-der. Characterized by pathogenic immunoglobulin G (IgG) antibodies against MOG, a potential treatment strategy for MOGAD is to reduce circulating IgG levels, e.g., by interference with the IgG recycling pathway mediated by the neonatal Fc receptor (FcRn). Although the optic nerve is often detrimentally involved in MOGAD, the effect of FcRn blockade on the visual pathway has not been assessed. Our objective was to investigate effects of a monoclonal an-ti-FcRn antibody in murine MOG-IgG–associated experimental autoimmune encephalomyelitis (EAE).
Methods We induced active MOG35-55 EAE in C57Bl/6 mice followed by the application of a monoclonal MOG-IgG (8-18C5) 10 days postimmunization (dpi). Animals were treated with either a specific monoclonal antibody against FcRn (α-FcRn, 4470) or an isotype-matched control IgG on 7, 10, and 13 dpi. Neurologic disability was scored daily on a 10-point scale. Visual acuity was assessed by optomotor reflex. Histopathologic hallmarks of disease were as-sessed in the spinal cord, optic nerve, and retina. Immune cell infiltration was visualized by immunohistochemistry, demyelination by Luxol fast blue staining and complement deposition and number of retinal ganglion cells by im-munofluorescence.
Results In MOG-IgG–augmented MOG35-55 EAE, anti-FcRn treatment significantly attenuated neurologic disability over the course of disease (mean area under the curve and 95% confidence intervals (CIs): α-FcRn [n = 27], 46.02 [37.89–54.15]; isotype IgG [n = 24], 66.75 [59.54–73.96], 3 independent experiments), correlating with reduced amounts of demyelination and macrophage infiltration into the spinal cord. T- and B-cell infiltration and comple-ment deposition remained unchanged. Compared with isotype, anti-FcRn treatment prevented reduction of visual acuity over the course of disease (median cycles/degree and interquartile range: α-FcRn [n = 16], 0.50 [0.48–0.55] to 0.50 [0.48–0.58]; isotype IgG [n = 17], 0.50 [0.49–0.54] to 0.45 [0.39–0.51]).
Discussion We show preserved optomotor response and ameliorated course of disease after anti-FcRn treatment in an experimental model using a monoclonal MOG-IgG to mimic MOGAD. Selectively targeting FcRn might represent a promising therapeutic approach in MOGAD.
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- Multiple Sclerosis>
Nature Aging (Apr 15, 2021)
Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline
Groh J, Knöpper K, Arampatzi P, Yuan X, Lößlein L, Saliba AE, Kastenmüller W, Martini R
DOI: 10.1038/s43587-021-00049-z >>
Journal Club
Aging is often associated with damages and degeneration to the peripheral and central nervous system. Groh et al show that CD8+ T lymphocytes are causally involved in driving axon degeneration in the CNS in aging mice, a process that is further aggravated in aged mice by systemic inflammation. Functionally, these changes are also manifested in the visual system and Groh et al monitored them with our OptoDrum. Targeting such T cells may be a promising treatment against age-related decline of brain function.
Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon–myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages—important representatives of the innate immune system—are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses. Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes. Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function.
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The Journal of Immunology (Apr 12, 2021)
Conditional Deletions of Hdc Confirm Roles of Histamine in Anaphylaxis and Circadian Activity but Not in Autoimmune Encephalomyelitis
Morin F, Singh N, Mdzomba JB, Dumas A, Pernet V, Vallières L
DOI: 10.4049/jimmunol.2000719 >>
Experimental autoimmune encephalomyelitis (EAE) is the most widely used animal model for multiple sclerosis (MS), an autoimmune disease where the immune system attacks myelin, which coats neurons in the CNS. Histamine has been thought to play a role in MS, effecting disease progression either positively or negatively, depending on the location of histamine action. In this study, Morin et al created a conditional mouse KO model of Hdc, the enzyme that synthesizes histamine, and induced EAE in these mice. Surprisingly, while some phenotypes in these mice were consistent with the lack of histamine, it had no impact on the development and severity of EAE. One behavioral readout of the disease progression in EAE is the decline of visual acuity, which can be measured with our OptoDrum. Consistent with the other observation, visual acuity declined in EAE Hdc-KO animals in the same way as in EAE Hdc-WT animals.
Histamine is best known for its role in allergies, but it could also be involved in autoimmune diseases such as multiple sclerosis. However, studies using experimental autoimmune encephalomyelitis (EAE), the most widely used animal model for multiple sclerosis, have reported conflicting observations and suggest the implication of a nonclassical source of histamine. In this study, we demonstrate that neutrophils are the main producers of histamine in the spinal cord of EAE mice. To assess the role of histamine by taking into account its different cellular sources, we used CRISPR-Cas9 to generate conditional knockout mice for the histamine-synthesizing enzyme histidine decarboxylase. We found that ubiquitous and cell-specific deletions do not affect the course of EAE. However, neutrophil-specific deletion attenuates hypothermia caused by IgE-mediated anaphylaxis, whereas neuron-specific deletion reduces circadian activity. In summary, this study refutes the role of histamine in EAE, unveils a role for neutrophil-derived histamine in IgE-mediated anaphylaxis, and establishes a new mouse model to re-explore the inflammatory and neurologic roles of histamine.
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Brain Communications (Mar 03, 2021)
Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset
Groh J, Berve K, Martini R
DOI: 10.1093/braincomms/fcab047 >>
Journal Club
CLN disease, a subtype of Batten disease, is characterized by progressive neurodegeneration with onset in early childhood. This also affects vision. Some immunomodulatory drugs are clinically established to significantly attenuate the condition. Groh et al show in a mouse model of CLN1 that such treatment can help both when given before symptom onset, and to a lesser degree also during disease progression, by interfering with neuroinflammatory activity of immune cells.
Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative phenotype when applied preventively, i.e. before the development of substantial neural damage and clinical symptoms. Here, we show that in a mouse model for the early onset and rapidly progressing CLN1 form, more complex clinical phenotypes like disturbed motor coordination and impaired visual acuity are also ameliorated by immunomodulation. Moreover, we show that the disease outcome can be attenuated even when fingolimod and teriflunomide treatment starts after disease onset, i.e. when neurodegeneration is ongoing and clinical symptoms are detectable. In detail, treatment with either drug led to a reduction in T-cell numbers and microgliosis in the CNS, although not to the same extent as upon preventive treatment. Pharmacological immunomodulation was accompanied by a reduction of axonal damage, neuron loss and astrogliosis in the retinotectal system and by reduced brain atrophy. Accordingly, the frequency of myoclonic jerks and disturbed motor coordination were attenuated. Overall, disease alleviation was remarkably substantial upon therapeutic treatment with both drugs, although less robust than upon preventive treatment. To test the relevance of putative immune-independent mechanisms of action in this model, we treated CLN1 mice lacking mature T- and B-lymphocytes. Immunodeficient CLN1 mice showed, as previously reported, an improved neurological phenotype in comparison with genuine CLN1 mice which could not be further alleviated by either of the drugs, reflecting a predominantly immune-related therapeutic mechanism of action. The present study supports and strengthens our previous view that repurposing clinically approved immunomodulators may alleviate the course of CLN1 disease in human patients, even though diagnosis usually occurs when symptoms have already emerged.
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Frontiers in Cell and Developmental Biology (Nov 06, 2020)
Abundant Neural circRNA Cdr1as Is Not Indispensable for Retina Maintenance
Chen XJ, Li ML, Wang YH, Mou H, Wu Z, Bao S, Xu ZH, Zhang H, Wang XY, Zhang CJ, Xue X, Jin ZB.
DOI: 10.3389/fcell.2020.565543 >>
The role of circular RNAs is not well understood, including Cdr1as, which is abundant in vertebrate retina. Chen et al show that CDR1as-KO mice had only minor deficits. Those included reduced contrast sensitivity, as measured with our OptoDrum. Overall, however, Cdr1as abundance is not required for retinal development and maintenance.
Cdr1as is the abundant circular RNA (circRNA) in human and vertebrate retinas. However, the role of Cdr1as in the retina remains unknown. In this study, we aimed to generate a Cdr1as knockout (KO) mouse model and investigate the retinal consequences of Cdr1as loss of function. Through in situ hybridization (ISH), we demonstrated that Cdr1as is mainly expressed in the inner retina. Using CRISPR/Cas9 targeting Cdr1as, we successfully generated KO mice. We carried out ocular examinations in the KO mice until postnatal day 500. Compared with the age-matched wild-type (WT) siblings, the KO mice displayed increased b-wave amplitude of photopic electrophysiological response and reduced vision contrast sensitivity. Through small RNA profiling of the retinas, we determined that miR-7 was downregulated, while its target genes were upregulated. Taken together, our results demonstrated for the first time that Cdr1as ablation led to a mild retinal consequence in mice, indicating that Cdr1as abundance is not indispensable for retinal development and maintenance.
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Neurobiology of Aging (Nov 02, 2020)
Tau modulates visual plasticity in adult and old mice
Rodriguez L, Joly S, Zine-Eddine F, Mdzomba JB, Pernet V
DOI: 10.1016/j.neurobiolaging.2020.07.024 >>
Tau, a protein known to be involved in Alzheimer’s disease, has elusive functionality in the healthy CNS. Using behavioral measurements with our OptoDrum as a readout, Rodriguez et al could show that Tau is involved in adaptive plasticity in the adult brain, in response to changes in sensory experience.
Tau is a microtubule-associated protein involved in Alzheimer's disease. However, little is known on its physiological function in the healthy central nervous system. Here, we observed that the expression of Tau isoforms was modulated by neuronal maturation and visual experience in the mouse retina and in the visual cortex. The visual function of wild-type (WT) and Tau knockout (KO) mice was evaluated using the optokinetic reflex (OKR), an innate visuomotor behavior, and by electroretinography. Visual tests did not reveal functional impairments in young adult and old Tau KO animals. Moreover, monocular deprivation (MD) was used to increase OKR sensitivity, a plasticity phenomenon depending on the visual cortex. MD-induced OKR sensitivity enhancement was significantly stronger in Tau KO than in WT mice suggesting that Tau restricts visual plasticity. In addition, human Tau expression did not affect visual function and plasticity in a mouse tauopathy model, relative to WT controls. Our results unveil a novel function for Tau in the adaptive mechanisms of plasticity operating in the adult brain subjected to sensory experience changes.
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Journal of Neuroinflammation (Oct 28, 2020)
Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice
Berve K, West BL, Martini R, Groh J
DOI: 10.1186/s12974-020-01996-x >>
Neuroinflammation can have devastating degenerative consequences in the central nervous system when the immune system attacks the body’s own cells. This paper shows that neuroinflammation can be attenuated by treatment with proper pharmacological substances. This has beneficial consequences from the cellular to the behavioral level. For example, Berve et al show with our OptoDrum that vision degenerates strongly in Ppt1-/- mice due to optic nerve atrophy. Pharmacological inhibition of innate immune cells ameliorates those effects.
Background. The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice.
Methods. We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry.
Results. We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS.
Conclusions. Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.
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- Rare Disease>
Human Molecular Genetics (Apr 15, 2020)
Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations
Eckhardt J, Bachmann C, Benucci S, Elbaz M, Ruiz A, Zorzato F, Treves S
DOI: 10.1093/hmg/ddaa056 >>
Human congenital myopathies are most commonly caused by mutations in the RYR1 gene, encoding for a muscular calcium channel. In a corresponding mouse model, this study investigates the molecular basis of the
eye muscle phenotype which is part of the congenital myopathy. In the mutants, the altered calcium homeostasis and reduced calcium released by muscle fibres in the extraocular muscles lead to reduced activity of the eye muscles during development. This causes mis-expression of Myelin heavy chain (MyHC) isoforms, lack of the isoform MyHC-EO, myofibrillar disorganization, displacement and decreased number of mitochondria.
Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle (EOM) involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for Ryr1 mutations. Ex vivo force production in EOMs from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared with that observed in wild-type, single heterozygous mutant carriers or homozygous RyR1p.A4329D mice. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle-specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the EOM phenotype caused by the RyR1p.Q1970fsX16+p.A4329D compound heterozygous Ryr1 mutations is complex and due to a combination of modifications including a direct effect on the macromolecular complex involved in calcium release and indirect effects on the expression of myosin heavy chain isoforms.
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Molecular Therapy | Methods & Clinical Development (Mar 13, 2020)
Empowering Retinal Gene Therapy with a Specific Promoter for Human Rod and Cone ON-Bipolar Cells
Hulliger EC, Hostettler SM, Kleinlogel S
DOI: 10.1016/j.omtm.2020.03.003 >>
Journal Club
The authors present a crucial missing piece on the way to healing blindness: they describe a new promoter that can efficiently drive gene expression in human ON bipolar cells. Previous promotors worked well in mouse retina, but not in human retina. The new findings can pave the way to optogenetic gene therapy in blind human patients to restore functional vision. In this paper, Hulliger et al use our OptoDrum and show functional vision restoration in the rd1 mouse, a mouse model for Retinitis pigmentosa, at normal everyday light levels.
Optogenetic gene therapy holds promise to restore high-quality vision in blind patients and recently reached clinical trials. Although the ON-bipolar cells, the first retinal interneurons, make the most attractive targets for optogenetic vision restoration, they have remained inaccessible to human gene therapy due to the lack of a robust cell-specific promoter. We describe the design and functional evaluation of 770En_454P(hGRM6), a human GRM6 gene-derived, short promoter that drives strong and highly specific expression in both the rod- and cone-type ON-bipolar cells of the human retina. Expression also in cone-type ON-bipolar cells is of importance, since the cone-dominated macula mediates high-acuity vision and is the primary target of gene therapies. 770En_454P(hGRM6)-driven middle-wave opsin expression in ON-bipolar cells achieved lasting restoration of high visual acuity in the rd1 mouse model of late retinal degeneration. The new promoter enables precise manipulation of the inner retinal network and paves the way for clinical application of gene therapies for high-resolution optogenetic vision restoration, raising hopes of significantly improving the life quality of people suffering from blindness.
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- Retinal Degeneration>
Cell Death & Disease (Feb 06, 2020)
Nogo-A-targeting antibody promotes visual recovery and inhibits neuroinflammation after retinal injury
Baya Mdzomba J, Joly S, Rodriguez L, Dirani A, Lassiaz P, Behar-Cohen F, Pernet V
DOI: 10.1038/s41419-020-2302-x >>
Journal Club
Nogo-A is a potent myelin-associated inhibitor of neuronal growth and nervous system plasticity. It may be involved in many ocular diseases by preventing healing and recovery after physiological insults. This study shows that antibodies directed against Nogo-A promoted recovery after retinal injury. Baya Mdzomba et al monitor the visual acuity of the treated mice with our OptoDrum which provided a non-invasive readout of the injury and recovery, and enabled the researchers to get daily measurements of disease progression.
N-Methyl-D-aspartate (NMDA)-induced neuronal cell death is involved in a large spectrum of diseases affecting the brain and the retina such as Alzheimer’s disease and diabetic retinopathy. Associated neurological impairments may result from the inhibition of neuronal plasticity by Nogo-A. The objective of the current study was to determine the contribution of Nogo-A to NMDA excitotoxicity in the mouse retina. We observed that Nogo-A is upregulated in the mouse vitreous during NMDA-induced inflammation. Intraocular injection of a function-blocking antibody specific to Nogo-A (11C7) was carried out 2 days after NMDA-induced injury. This treatment significantly enhanced visual function recovery in injured animals. Strikingly, the expression of potent pro-inflammatory molecules was downregulated by 11C7, among which TNFα was the most durably decreased cytokine in microglia/macrophages. Additional analyses suggest that TNFα downregulation may stem from cofilin inactivation in microglia/macrophages. 11C7 also limited gliosis presumably via P.Stat3 downregulation. Diabetic retinopathy was associated with increased levels of Nogo-A in the eyes of donors. In summary, our results reveal that Nogo-A-targeting antibody can stimulate visual recovery after retinal injury and that Nogo-A is a potent modulator of excitotoxicity-induced neuroinflammation. These data may be used to design treatments against inflammatory eye diseases.
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eLife (Dec 11, 2019)
Rod nuclear architecture determines contrast transmission of the retina and behavioral sensitivity in mice
Subramanian K, Weigert M, Borsch O, Petzold H, Garcia-Ulloa A, Myers EW, Ader M, Solovei I, Kreysing M
DOI: 10.7554/eLife.49542 >>
Journal Club
The chromatin in the nucleus of rod photoreceptors has an inverted structure in nocturnal animals. Metabolically, this is expensive to maintain, so it has been proposed that the inverted architecture provides an advantage during night vision. Subramanian et al could show with our OptoDrum that the inverted nuclear architecture provides improved contrast sensitivity in dark environments.
Rod photoreceptors of nocturnal mammals display a striking inversion of nuclear architecture, which has been proposed as an evolutionary adaptation to dark environments. However, the nature of visual benefits and the underlying mechanisms remains unclear. It is widely assumed that improvements in nocturnal vision would depend on maximization of photon capture at the expense of image detail. Here, we show that retinal optical quality improves 2-fold during terminal development, and that this enhancement is caused by nuclear inversion. We further demonstrate that improved retinal contrast transmission, rather than photon-budget or resolution, enhances scotopic contrast sensitivity by 18–27%, and improves motion detection capabilities up to 10-fold in dim environments. Our findings therefore add functional significance to a prominent exception of nuclear organization and establish retinal contrast transmission as a decisive determinant of mammalian visual perception.
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Journal of Vision (Feb 01, 2019)
The contrast sensitivity function of a small cryptobenthic marine fish
Santon M, Münch TA, Michiels NK
DOI: 10.1167/19.2.1 >>
Journal Club
Application of our OptoDrum measurements to a small bottom-dwelling fish shows that these fish feature excellent contrast sensitivity.
Spatial resolution is a key property of eyes when it comes to understanding how animals' visual signals are perceived. This property can be robustly estimated by measuring the contrast sensitivity as a function of different spatial frequencies, defined as the number of achromatic vertical bright and dark stripe pairs within one degree of visual angle. This contrast sensitivity function (CSF) has been estimated for different animal groups, but data on fish are limited to two free-swimming, freshwater species (i.e., goldfish and bluegill sunfish). In this study, we describe the CSF of a small marine cryptobenthic fish (Tripterygion delaisi) using an optokinetic reflex approach. Tripterygion delaisi features a contrast sensitivity that is as excellent as other fish species, up to 125 (reciprocal of Michelson contrast) at the optimal spatial frequency of 0.375 c/°. The maximum spatial resolution is instead relatively coarse, around 2.125 c/°. By comparing our results with acuity values derived from anatomical estimates of ganglion cells' density, we conclude that the optokinetic reflex seems to be adapted to process low spatial frequency information from stimuli in the peripheral visual field and show that small marine fish can feature excellent contrast sensitivity at optimal spatial frequency.
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Type: Cornerstone_Looper_Provider_Terms Size: 1 Current Data: array(1) { [0]=> bool(false) }
The Journal of Comparative Neurology (Dec 15, 2015)
Effects of the jimpy mutation on mouse retinal structure and function
Hovhannisyan A, Benkner B, Biesemeier A, Schraermeyer U, Kukley M, Münch TA
DOI: 10.1002/cne.23818 >>
The Jimpy mutant mouse has no myelination in the central nervous system, including of axons in the optic nerve. Despite severe consequences such as seizures and motor deficits, and early death at around P20, the lack of myelination has no major consequences on the early development of retinal morphology or function, and they show normal optomotor visual behavior.
The Jimpy mutant mouse has a point mutation in the proteolipid protein gene (plp1). The resulting misfolding of the protein leads to oligodendrocyte death, myelin destruction, and failure to produce adequately myelinated axons in the central nervous system (CNS). It is not known how the absence of normal myelination during development influences neural function. We characterized the Jimpy mouse retina to find out whether lack of myelination in the optic nerve during development has an effect on normal functioning and morphology of the retina. Optokinetic reflex measurements showed that Jimpy mice had, in general, a functional visual system. Both PLP1 antibody staining and reverse transcriptase-polymerase chain reaction for plp1 mRNA showed that plp1 is not expressed in the wild-type retina. However, in the optic nerve, plp1 is normally expressed, and consequently, in Jimpy mutant mice, myelination of axons in the optic nerve was mostly absent. Nevertheless, neither axon count nor axon ultrastructure in the optic nerve was affected. Physiological recordings of ganglion cell activity using microelectrode arrays revealed a decrease of stimulus-evoked activity at mesopic light levels. Morphological analysis of the retina did not show any significant differences in the gross morphology, such as thickness of retinal layers or cell number in the inner and outer nuclear layer. The cell bodies in the inner nuclear layer, however, were larger in the peripheral retina of Jimpy mutant mice. Antibody labeling against cell type-specific markers showed that the number of rod bipolar and horizontal cells was increased in Jimpy mice. In conclusion, whereas the Jimpy mutation has dramatic effects on the myelination of retinal ganglion cell axons, it has moderate effects on retinal morphology and function.
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- Neuroinflammation·
- Rare Disease>
Investigative Ophthalmology & Visual Science (Aug 07, 2014)
Characterization of a mouse model with complete RPE loss and its use for RPE cell transplantation
Carido M, Zhu Y, Postel K, Benkner B, Cimalla P, Karl MO, Kurth T, Paquet-Durand F, Koch E, Münch TA, Tanaka EM, Ader M
DOI: 10.1167/iovs.14-14325 >>
Carido et al present the sodium iodate mouse model of age-related macular degeneration. Systemic injection of sodium iodate leads to death of retinal pigment epithelium, with subsequent photoreceptor cell death. OptoDrum measurements show that the vision loss can be tracked at the behavioral level.
Purpose: Age-related macular degeneration (AMD) is a major leading cause of visual impairment and blindness with no cure currently established. Cell replacement of RPE is discussed as a potential therapy for AMD. Previous studies were performed in animal models with severe limitations in recapitulating the disease progression. In detail, we describe the effect of systemic injection of sodium iodate in the mouse retina. We further evaluate the useful-ness of this animal model to analyze cell-specific effects following transplantation of human embryonic stem cell (hESC)-derived RPE cells.
Methods: Morphologic, functional, and behavioral changes following sodium iodate injection were monitored by histology, gene expression analysis, electroretinography, and optokinetic head tracking. Human embryonic stem cell–derived RPE cells were transplanted 1 week after sodium iodate injection and experimental retinae were ana-lyzed 3 weeks later.
Results: Injection of sodium iodate caused complete RPE cell loss, photoreceptor degeneration, and altered gene and protein expression in outer and inner nuclear layers. Retinal function was severely affected by day 3 and abol-ished from day 14. Following transplantation, donor hESC-derived RPE cells formed extensive monolayers that dis-played wild-type RPE cell morphology, organization, and function, including phagocytosis of host photoreceptor outer segments.
Conclusions: Systemic injection of sodium iodate has considerable effects on RPE, photoreceptors, and inner nu-clear layer neurons, and provides a model to assay reconstitution and maturation of RPE cell transplants. The avail-ability of an RPE-free Bruch's membrane in this model likely allows the unprecedented formation of extensive polar-ized cell monolayers from donor hESC-derived RPE cell suspensions.
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- Sodium Iodate>
Behavioral Neuroscience (Aug 19, 2013)
Characterizing visual performance in mice: an objective and automated system based on the optokinetic reflex
Benkner B, Mutter M, Ecke G, Münch TA
DOI: 10.1037/a0033944 >>
Journal Club
In this paper, Benkner et al introduced the algorithm underlying the optomotor measurements in what later would become the OptoDrum. Proof-of-concept data is presented with wild-type and rd10 retinal degeneration mice.
Testing optokinetic head or eye movements is an established method to determine visual performance of laboratory animals, including chickens, guinea pigs, mice, or fish. It is based on the optokinetic reflex which causes the ani-mals to track a drifting stripe pattern with eye and head movements. We have developed an improved version of the optomotor test with better control over the stimulus parameters, as well as a high degree of automation. The stripe pattern is presented on computer monitors surrounding the animal. By tracking the head position of freely moving animals in real time, the visual angle under which the stripes of the pattern appeared was kept constant even for changing head positions. Furthermore, an algorithm was developed for automated evaluation of the track-ing performance of the animal. Comparing the automatically determined behavioral score with manual assessment of the animals’ tracking behavior confirmed the reliability of our methodology. As an example, we reproduced the known contrast sensitivity function of wild type mice. Furthermore, the progressive decline in visual performance of a mouse model of retinal degeneration, rd10, was demonstrated.
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- Retinal Degeneration>