Retinoschisin is linked to retinal Na/K-ATPase signaling and localization

Plössl, Karolina; Royer, Melanie; Bernklau, Sarah; Tavraz, Neslihan N.; Friedrich, Thomas; Wild, Jens; Weber, Bernhard H. F.; Friedrich, Ulrike

doi:10.1091/mbc.e17-01-0064

Cited by 30 publications

(59 citation statements)

References 73 publications

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“…These defects were observed at a frequency of roughly 4% relative to the total rod photoreceptor population. To further examine these defects, we stained IS membrane with Na/K ATPase (23,24) and OS with rhodopsin. MPC KO retinas formed small vacuoles in the IS and IS-OS junction ( Fig.…”

Section: Mpc-deficient Retinas Have Distinctive Ultrastructural Defectsmentioning

confidence: 99%

Loss of MPC1 reprograms retinal metabolism to impair visual function

Grenell

Wang

Yam

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

118

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Glucose metabolism in vertebrate retinas is dominated by aerobic glycolysis (the “Warburg Effect”), which allows only a small fraction of glucose-derived pyruvate to enter mitochondria. Here, we report evidence that the small fraction of pyruvate in photoreceptors that does get oxidized by their mitochondria is required for visual function, photoreceptor structure and viability, normal neuron–glial interaction, and homeostasis of retinal metabolism. The mitochondrial pyruvate carrier (MPC) links glycolysis and mitochondrial metabolism. Retina-specific deletion of MPC1 results in progressive retinal degeneration and decline of visual function in both rod and cone photoreceptors. Using targeted-metabolomics and 13C tracers, we found that MPC1 is required for cytosolic reducing power maintenance, glutamine/glutamate metabolism, and flexibility in fuel utilization.

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Section: Mpc-deficient Retinas Have Distinctive Ultrastructural Defectsmentioning

confidence: 99%

Loss of MPC1 reprograms retinal metabolism to impair visual function

Grenell

Wang

Yam

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

118

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“…20,21 Page 4 of 33 Recent studies showed that RS1 regulates Erk signaling and apoptosis in retinal cells while also exerting regulatory effects on Na + /K + -ATPase signaling and localization. 22,23 Despite advances in understanding XLRS pathophysiology, 6,15,24,25 the factors underlying the heterogeneity of clinical phenotypes in terms of disease onset, symptoms, severity, and progression, as seen even between family members have not been entirely clear.…”

Section: Introductionmentioning

confidence: 99%

Genetic Rescue of X-Linked Retinoschisis Mouse (Rs1^−/y) Retina Induces Quiescence of the Retinal Microglial Inflammatory State Following AAV8-RS1 Gene Transfer and Identifies Gene Networks Underlying Retinal Recovery

Vijayasarathy¹,

Zeng²,

Brooks³

et al. 2021

Human Gene Therapy

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To understand RS1 gene interaction networks in the X-linked retinoschisis (XLRS) mouse retina ( Rs1 −/y ), we analyzed the transcriptome by RNA sequencing before and after in vivo expression of exogenous retinoschisin ( RS1 ) gene delivered by AAV8. RS1 is a secreted cell adhesion protein that is critical for maintaining structural lamination and synaptic integrity of the neural retina. RS1 loss-of-function mutations cause XLRS disease in young boys and men, with splitting (“schisis”) of retinal layers and synaptic dysfunction that cause progressive vision loss with age. Analysis of differential gene expression profiles and pathway enrichment analysis of Rs1 -KO ( Rs1 −/y ) retina identified cell surface receptor signaling and positive regulation of cell adhesion as potential RS1 gene interaction networks. Most importantly, it also showed massive dysregulation of immune response genes at early age, with characteristics of a microglia-driven proinflammatory state. Delivery of AAV8- RS1 primed the Rs1 -KO retina toward structural and functional recovery. The disease transcriptome transitioned toward a recovery phase with upregulation of genes implicated in wound healing, anatomical structure (camera type eye) development, metabolic pathways, and collagen IV networks that provide mechanical stability to basement membrane. AAV8- RS1 expression also attenuated the microglia gene signatures to low levels toward immune quiescence. This study is among the first to identify RS1 gene interaction networks that underlie retinal structural and functional recovery after RS1 gene therapy. Significantly, it also shows that providing wild-type RS1 gene function caused the retina immune status to transition from a degenerative inflammatory phenotype toward immune quiescence, even though the transgene is not directly linked to microglia function. This study indicates that inhibition of microglial proinflammatory responses is an integral part of therapeutic rescue in XLRS gene therapy, and gene therapy might realize its full potential if delivered before microglia activation and photoreceptor cell death. Clinical Trials. gov Identifier NTC 02317887.

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“…Retinoschisin, a 224 amino acid protein, is secreted from photoreceptors and bipolar cells in retina and has been shown to be crucial for cell adhesion during retinal development [ 18 ]. It has been suggested that retinoschisin may also be involved in mitogen-activated protein kinase signaling and apoptosis in retina [ 18 ] and recently has been shown to influence Na/K-ATPase signaling and localization [ 19 ]. Employing cryo-electron microscopy, it has been discovered that functional retinoschisin forms a dimer of octamer rings comprising a hexadecamer.…”

Section: Introductionmentioning

confidence: 99%

Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant

et al. 2018

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BackgroundTo describe the clinical phenotype and genetic cause underlying the disease pathology in a pedigree (affected n = 9) with X-linked retinoschisis (XLRS1) due to a novel RS1 mutation and to assess suitability for novel therapies using multimodal imaging.MethodsThe Irish National Registry for Inherited Retinal Degenerations (Target 5000) is a program including clinical history and examination with multimodal retinal imaging, electrophysiology, visual field testing and genetic analysis. Nine affected patients were identified across 3 generations of an XLRS1 pedigree. DNA sequencing was performed for each patient, one carrier female and one unaffected relative. Pedigree mapping revealed a further 4 affected males.ResultsAll affected patients had a history of reduced visual acuity and dyschromatopsia; however, the severity of phenotype varied widely between the nine affected subjects. The stage of disease was classified as previously described. Phenotypic severity was not linearly correlated with age. A novel RS1 (Xp22.2) mutation was detected (NM_000330: c.413C > A) resulting in a p.Thr138Asn substitution. Protein modelling demonstrated a change in higher order protein folding that is likely pathogenic.ConclusionsThis family has a novel gene mutation in RS1 with clinical evidence of XLRS1. A proportion of the older generation has developed end-stage macular atrophy; however, the severity is variable. Confirmation of genotype in the affected grandsons of this pedigree in principle may enable them to avail of upcoming gene therapies, provided there is anatomical evidence (from multimodal imaging) of potentially reversible early stage disease.

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Retinoschisin is linked to retinal Na/K-ATPase signaling and localization

Cited by 30 publications

References 73 publications

Loss of MPC1 reprograms retinal metabolism to impair visual function

Loss of MPC1 reprograms retinal metabolism to impair visual function

Genetic Rescue of X-Linked Retinoschisis Mouse (Rs1^−/y) Retina Induces Quiescence of the Retinal Microglial Inflammatory State Following AAV8-RS1 Gene Transfer and Identifies Gene Networks Underlying Retinal Recovery

Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant

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Retinoschisin is linked to retinal Na/K-ATPase signaling and localization

Cited by 30 publications

References 73 publications

Loss of MPC1 reprograms retinal metabolism to impair visual function

Loss of MPC1 reprograms retinal metabolism to impair visual function

Genetic Rescue of X-Linked Retinoschisis Mouse (Rs1−/y) Retina Induces Quiescence of the Retinal Microglial Inflammatory State Following AAV8-RS1 Gene Transfer and Identifies Gene Networks Underlying Retinal Recovery

Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant

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Genetic Rescue of X-Linked Retinoschisis Mouse (Rs1^−/y) Retina Induces Quiescence of the Retinal Microglial Inflammatory State Following AAV8-RS1 Gene Transfer and Identifies Gene Networks Underlying Retinal Recovery