Replenishment of TCA cycle intermediates provides photoreceptor resilience against neurodegeneration during progression of retinitis pigmentosa.
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ABSTRACT:
SUBMITTER: Rowe AA
PROVIDER: S-EPMC8492344 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hereditary retinal degenerative diseases, such as retinitis pigmentosa (RP), are characterized by the progressive loss of rod photoreceptors followed by loss of cones. While retinal gene therapy clinical trials demonstrated temporary improvement in visual function, this approach has yet to achieve sustained functional and anatomical rescue after disease onset in patients. The lack of sustained benefit could be due to insufficient transduction efficiency of viral vectors ("too little") and/or because the disease is too advanced ("too late") at the time therapy is initiated. Here, we tested the latter hypothesis and developed a mouse RP model that permits restoration of the mutant gene in all diseased photoreceptor cells, thereby ensuring sufficient transduction efficiency. We then treated mice at early, mid, or late disease stages. At all 3 time points, degeneration was halted and function was rescued for at least 1 year. Not only do our results demonstrate that gene therapy effectively preserves function after the onset of degeneration, our study also demonstrates that there is a broad therapeutic time window. Moreover, these results suggest that RP patients are treatable, despite most being diagnosed after substantial photoreceptor loss, and that gene therapy research must focus on improving transduction efficiency to maximize clinical impact.
| S-EPMC4588299 | biostudies-literature
Project description:The purpose of this study was to examine cone photoreceptor structure in retinitis pigmentosa (RP) and Usher syndrome using confocal and nonconfocal split-detector adaptive optics scanning light ophthalmoscopy (AOSLO).Nineteen subjects (11 RP, 8 Usher syndrome) underwent ophthalmic and genetic testing, spectral-domain optical coherence tomography (SD-OCT), and AOSLO imaging. Split-detector images obtained in 11 subjects (7 RP, 4 Usher syndrome) were used to assess remnant cone structure in areas of altered cone reflectivity on confocal AOSLO.Despite normal interdigitation zone and ellipsoid zone appearance on OCT, foveal and parafoveal cone densities derived from confocal AOSLO images were significantly lower in Usher syndrome compared with RP. This was due in large part to an increased prevalence of non-waveguiding cones in the Usher syndrome retina. Although significantly correlated to best-corrected visual acuity and foveal sensitivity, cone density can decrease by nearly 38% before visual acuity becomes abnormal. Aberrantly waveguiding cones were noted within the transition zone of all eyes and corresponded to intact inner segment structures. These remnant cones decreased in density and increased in diameter across the transition zone and disappeared with external limiting membrane collapse.Foveal cone density can be decreased in RP and Usher syndrome before visible changes on OCT or a decline in visual function. Thus, AOSLO imaging may allow more sensitive monitoring of disease than current methods. However, confocal AOSLO is limited by dependence on cone waveguiding, whereas split-detector AOSLO offers unambiguous and quantifiable visualization of remnant cone inner segment structure. Confocal and split-detector thus offer complementary insights into retinal pathology.
| S-EPMC5089122 | biostudies-literature
Project description:The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin's stabilization of rod outer segments (ROS). Homozygous E150K (KK) mice exhibited early-onset retinal degeneration, with disorganized ROS structures, autofluorescent deposits in the subretinal space, and aberrant photoreceptor phagocytosis. Heterozygous (EK) mice displayed a delayed-onset milder retinal degeneration. Further, mutant receptors were mislocalized to the inner segments and perinuclear region. Though KK mouse rods displayed markedly decreased phototransduction, biochemical studies of the mutant rhodopsin revealed only minimally affected chromophore binding and G protein activation. Ablation of the chromophore by crossing KK mice with mice lacking the critical visual cycle protein LRAT slowed retinal degeneration, whereas blocking phototransduction by crossing KK mice with GNAT1-deficient mice slightly accelerated this process. This study highlights the importance of proper higher-order organization of rhodopsin in the native tissue and provides information about the signaling properties of this mutant rhodopsin. Additionally, these results suggest that patients heterozygous for the E150K mutation should be periodically reevaluated for delayed-onset retinal degeneration.
| S-EPMC3533307 | biostudies-literature
Project description:The outer segments of rod and cone photoreceptor cells are highly specialized sensory cilia made up of hundreds of membrane discs stacked into an orderly array along the photoreceptor axoneme. It is not known how the alignment of the outer segment discs is controlled, although it has been suggested that the axoneme may play a role in this process. Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of retinitis pigmentosa (RP). Disruption of the Rp1 gene in mice causes misorientation of outer segment discs, suggesting a role for RP1 in outer segment organization. Here, we show that the RP1 protein is part of the photoreceptor axoneme. Amino acids 28-228 of RP1, which share limited homology with the microtubule-binding domains of the neuronal microtubule-associated protein (MAP) doublecortin, mediate the interaction between RP1 and microtubules, indicating that the putative doublecortin (DCX) domains in RP1 are functional. The N-terminal portion of RP1 stimulates the formation of microtubules in vitro and stabilizes cytoplasmic microtubules in heterologous cells. Evaluation of photoreceptor axonemes from mice with targeted disruptions of the Rp1 gene shows that Rp1 proteins that contain the DCX domains also help control axoneme length and stability in vivo. These results demonstrate that RP1 is a MAP. Given the specific expression of RP1 in photoreceptors, RP1 is thus the first photoreceptor-specific MAP to be identified. Furthermore, these findings indicate that the RP1 form of inherited retinal degeneration is part of the larger class of neurodegenerative diseases caused by MAP dysfunction.
| S-EPMC1904502 | biostudies-literature
Project description:Luteolin is neuroprotective for retinal ganglion cells and retinal pigment epithelial cells after oxidative injury, whereby it can inhibit microglial neurotoxicity. Therefore, luteolin holds the potential to be useful for treatment of retinal diseases. The purpose of this study was to investigate whether luteolin exhibits neuroprotective effects on rod cells in rd10 mice, a slow photoreceptor-degenerative model of retinitis pigmentosa. Luteolin (100 mg/kg) intraperitoneally injected daily from postnatal day 14 (P14) to P25 significantly enhanced the visual performance and retinal light responses of rd10 mice at P25. Moreover, it increased the survival of photoreceptors and improved retinal structure. Mechanistically, luteolin treatment attenuated increases in reactive oxygen species, photoreceptor apoptosis, and reactive gliosis; increased mRNA levels of anti-inflammatory cytokines while lowering that of pro-inflammatory and chemoattractant cytokines; and lowered the ratio of phospho-JNK/JNK. Application of the JNK inhibitor SP600125 exerted a similar protective effect to luteolin, suggesting that luteolin delays photoreceptor degeneration and functional deterioration in rd10 mice through regulation of retinal oxidation and inflammation by inhibiting the JNK pathway. Therefore, luteolin may be useful as a supplementary treatment for retinitis pigmentosa. This study was approved by the Qualified Ethics Committee of Jinan University, China (approval No. IACUC-20181217-02) on December 17, 2018.
| S-EPMC8343326 | biostudies-literature
Project description:PurposeInherited retinal diseases affect the L-, M-, S-cones and rods in distinct ways, which calls for new methods that enable quantification of photoreceptor-specific functions. We tested the feasibility of using the silent substitution paradigm to estimate photoreceptor-driven temporal contrast sensitivity (tCS) functions in patients with retinitis pigmentosa.MethodsThe silent substitution paradigm is based on substitution of lights of different spectral composition; this offers considerable advantage over other stimulation techniques. We used a four-primary LED stimulator to create perifoveal annular stimuli (2° inner, 12° outer diameters) and used a triple silent substitution to probe photoreceptor-selective tCS. Measurements were performed in a heterogeneous cohort of 15 patients with retinitis pigmentosa and related to those in a control group of nine color-normal healthy observers. Age differences between groups were addressed with a model of age-related normal contrast sensitivity derived from measurements in 20 healthy observers aged between 23 and 83 years.ResultsThe age-related loss of tCS amounted to 0.1 dB/year in healthy subjects across all photoreceptor subtypes. In patients, tCS was decreased for every photoreceptor subtype; however, S-cone- and rod-driven sensitivities were most strongly affected. Postreceptoral mechanisms were not affected.ConclusionsThis feasibility study provides evidence that the silent substitution technique enables the estimation of photoreceptor-selective tCS functions and can serve as an accurate biomarker of photoreceptor-specific contrast sensitivity loss in patients with retinitis pigmentosa.Translational relevanceWe aim to develop tests of visual function for clinical trials of novel therapies for inherited retinal diseases from methods that can currently be used only in vision research labs.
| S-EPMC7409023 | biostudies-literature
Project description:For most neurodegenerative diseases the precise duration of an individual cell's death is unknown, which is an obstacle when counteractive measures are being considered. To address this, we used the rd1 mouse model for retinal neurodegeneration, characterized by phosphodiesterase-6 (PDE6) dysfunction and photoreceptor death triggered by high cyclic guanosine-mono-phosphate (cGMP) levels. Using cellular data on cGMP accumulation, cell death, and survival, we created mathematical models to simulate the temporal development of the degeneration. We validated model predictions using organotypic retinal explant cultures derived from wild-type animals and exposed to the selective PDE6 inhibitor zaprinast. Together, photoreceptor data and modeling for the first time delineated three major cell death phases in a complex neuronal tissue: (1) initiation, taking up to 36 h, (2) execution, lasting another 40 h, and finally (3) clearance, lasting about 7 h. Surprisingly, photoreceptor neurodegeneration was noticeably slower than necrosis or apoptosis, suggesting a different mechanism of death for these neurons.
| S-EPMC3593146 | biostudies-literature
Project description:Most of inherited retinal diseases such as retinitis pigmentosa (RP) cause photoreceptor cell death resulting in blindness. RP is a large family of diseases in which the photoreceptor cell death can be caused by a number of pathways. Among them, light exposure has been reported to induce photoreceptor cell death. However, the detailed mechanism by which photoreceptor cell death is caused by light exposure is unclear. In this study, we have shown that even a mild light exposure can induce ectopic phototransduction and result in the acceleration of rod photoreceptor cell death in some vertebrate models. In ovl, a zebrafish model of outer segment deficiency, photoreceptor cell death is associated with light exposure. The ovl larvae show ectopic accumulation of rhodopsin and knockdown of ectopic rhodopsin and transducin rescue rod photoreceptor cell death. However, knockdown of phosphodiesterase, the enzyme that mediates the next step of phototransduction, does not. So, ectopic phototransduction activated by light exposure, which leads to rod photoreceptor cell death, is through the action of transducin. Furthermore, we have demonstrated that forced activation of adenylyl cyclase in the inner segment leads to rod photoreceptor cell death. For further confirmation, we have also generated a transgenic fish which possesses a human rhodopsin mutation, Q344X. This fish and rd10 model mice show photoreceptor cell death caused by adenylyl cyclase. In short, our study indicates that in some RP, adenylyl cyclase is involved in photoreceptor cell death pathway; its inhibition is potentially a logical approach for a novel RP therapy.
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Project description:ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of ?2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNF? secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.
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Project description:1. The contribution of Co2 fixation to the anaplerotic mechanisms in the myocardium was investigated in isolated perfused rat hearts. 2. K+-induced arrest of the heart was used to elicit a transition in the concentrations of the intermediates of the tricarboxylic acid cycle. 3. Incorporation of 14C from [14]bicarbonate into tricarboxylic acid-cycle intermediates was measured and the rates of the reactions of the cycle were estimated by means of a linear optimization program which solves the differential equations describing a simulation model of the tricarboxylic acid cycle and related reactions. 4. The results showed that the rate of CO2 fixation is dependent on the metabolic state of the myocardium. Upon a sudden diminution of cellular ATP consumption, the pool size of the tricarboxylic acid-cycle metabolites increased and the rate of label incorporation from [14C]bicarbonate into the cycle metabolites increased simultaneously. The computer model was necessary to separate the rapid equilibration between bicarbonate and some metabolites from the potentially anaplerotic reactions. The main route of anaplerosis during metabolite accumulation was through malate + oxaloacetate. Under steady-state conditions there was a constant net outward flow from the tricarboxylic acid cycle via the malate + oxaloacetate pool, with a concomitant anaplerotic flow from metabolites forming succinyl-CoA (3-carboxypropionyl-CoA).
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