Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration

Charish, Jason; Shabanzadeh, Alireza P.; Chen, Danian; Mehlen, Patrick; Sethuramanujam, Santhosh; Harada, Hirofumi; Bonilha, Vera L.; Awatramani, Gautam B.; Bremner, Rod; Monnier, Philippe P.

doi:10.1172/jci125898

Cited by 15 publications

(15 citation statements)

References 81 publications

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“…We chose the time points for RNA-seq from the previously reported RP progress curve of Rho P23H/P23H mice [25]. RNA-seq identified DEGs (GFOLD >1.5) on the retinas of Rho P23H/P23H mice versus C57BL/6J (B6J) mice.…”

Section: Resultsmentioning

confidence: 99%

RNA-Seq Analysis for Exploring the Pathogenesis of Retinitis Pigmentosa in P23H Knock-In Mice

Li¹,

Du²,

Xu³

et al. 2021

Ophthalmic Res

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Introduction: Mechanisms contributing to the progression of autosomal dominant retinitis pigmentosa (adRP) due to the P23H rhodopsin mutation are complex and diverse. Previous studies showed that mechanisms like endoplasmic reticulum (ER) stress, pyroptosis, and oxidative stress were involved in the pathogenesis of the disease. However, the roles and relationships of different mechanisms are not precisely known. In this study, we aimed to evaluate certain mechanisms and find novel genes involved in P23H-related adRP. Methods: Total RNA extracted at postnatal day (PN) 14, PN21, and PN35 was used for RNA sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses were conducted for RNA-seq data. Additionally, data from the clustered regularly interspaced short palindromic repeats (CRISPR) screening library and the RNA-seq data of several mechanisms were used for generating custom gene sets for gene set enrichment analysis (GSEA). Next, we obtained the intersection of the aforementioned gene sets and our RNA-seq data to identify candidate genes, which were verified using real-time quantitative PCR (qPCR). Results: Functional enrichment analyses were consistent with disease phenotypes. All time points observed pyroptosis. In the results of GSEA, ER stress, pyroptosis, and oxidative stress were observed at PN14. ER stress and pyroptosis were shown on PN35. A total of 22 candidate genes were identified. The expression levels of selected genes verified by qPCR were concordant with the RNA-seq data. Conclusions: In our study, we conclude that pyroptosis and ER stress might play a central role in RP progression. We also identified differentially expressed gene clusters related to ER stress and pyroptosis, which deserve further study. These findings provide a novel perspective for the investigation of P23H-related adRP.

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Section: Resultsmentioning

confidence: 99%

RNA-Seq Analysis for Exploring the Pathogenesis of Retinitis Pigmentosa in P23H Knock-In Mice

Li¹,

Du²,

Xu³

et al. 2021

Ophthalmic Res

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“…Extracellular RGMa inhibits axon regeneration and therefore may accelerate demise of neurons [ 122 , 123 , 124 ]. However, targeting the RGMa pathway with antibodies or neutralization, respectively, antagonism of the neogenin receptor activity, may start regeneration not only in acute, but also in chronic inflammatory and neurodegenerative disorders [ 46 , 125 , 126 , 127 , 128 ] ( Figure 1 ). It is well known, that considerable metabolic similarities exist both in the peripheral and central nervous system.…”

Section: Discussionmentioning

confidence: 99%

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Müller

Mueller

Riederer

2021

Cells

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Symptomatic treatments are available for Parkinson’s disease and Alzheimer’s disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.

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“…2,8,13,22,[38][39][40][41][42][43][44][45][46][47][48] Most studies on retinal cell types have relied upon murine models, but many increasingly study human donor retinas 6,30,31,[48][49][50] , especially in order to profile retinal disease. 31,43,[50][51][52][53] Glaucoma, age-related macular dystrophy and retinal light damage have also been studied in murine models. 7,14,29,34,35,54,55 Some studies have grown cell lines in vitro from fetal retina 49, 56 , whereas other have used human pluripotent, induced pluripotent or embryonic stem cells to generate purified cell populations or retinal organoids.…”

Section: Previous Methods In Vivo and In Vitromentioning

confidence: 99%

Boolean Implication Analysis Improves Prediction Accuracy of In Silico Gene Reporting of Retinal Cell Types

Subramanian¹,

Sahoo

2020

Preprint

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The retina is a complex tissue containing multiple cell types that is essential for vision. Understanding the gene expression patterns of various retinal cell types has potential applications in regenerative medicine. Retinal organoids (optic vesicles) derived from pluripotent stem cells have begun to yield insights into the transcriptomics of developing retinal cell types in humans through single cell RNA-sequencing studies. Previous methods of gene reporting have relied upon techniques in vivo using microarray data, or correlational and dimension reduction methods for analyzing single cell RNA-sequencing data in silico. Here, we present a bioinformatic approach using Boolean implication to discover retinal cell type-specific genes. We apply this approach to previously published retina and retinal organoid datasets and improve upon previously published correlational methods. Our method improves the prediction accuracy and reproducibility of marker genes of retinal cell types and discovers several new high confidence cone and rod-specific genes. Furthermore, our method is general and can impact all areas of gene expression analyses in cancer and other human diseases.

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Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration

Cited by 15 publications

References 81 publications

RNA-Seq Analysis for Exploring the Pathogenesis of Retinitis Pigmentosa in P23H Knock-In Mice

RNA-Seq Analysis for Exploring the Pathogenesis of Retinitis Pigmentosa in P23H Knock-In Mice

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Boolean Implication Analysis Improves Prediction Accuracy of In Silico Gene Reporting of Retinal Cell Types

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