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Mechanisms of Inherited Retinal Degenerative Diseases and Emerging Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 8718

Special Issue Editors

1. Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
2. Department of Ophthalmology and Visual Neurosciences. University of Minnesota, Lions Research Building, 2001 6th St SE, Room 219, Minneapolis, MN 55455, USA

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Guest Editor
Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia

Special Issue Information

Dear Colleagues,

Blindness due to retinal diseases represents a huge socio-economic burden in both developed and developing nations worldwide, affecting the quality of life of an individual. Neurodegeneration, resulting from retinal neuronal cell death, has been primarily implicated in vision loss. The process of neurodegeneration is the underlying feature and a common cause of several degenerative diseases of the retina. These include glaucoma, diabetic retinopathy, age-related macular degeneration, and other forms of inherited retinal diseases. Inherited retinal degenerative diseases (RDDs) are a genetically and phenotypically heterogeneous group of visual disorders, which primarily affect the function of photoreceptor cells and are among the leading causes of clinical blindness in humans. Various biochemical pathways and genetic mechanisms are affected in the retina and photoreceptor cells of patients with retinal degenerative diseases. These include key genes and enzymes in the phototransduction pathway, protein trafficking, connecting cilium, lipid metabolism, retinal development, and synaptic function. Besides photoreceptor injury/death and retinal neurodegeneration, breakdown of the blood–retinal barrier, retinal pigmented epithelium (RPE) dysfunction and mitochondrial dysregulation also have a plausible critical role in retinal pathologies. Although much progress has been made when it comes to understanding the cause and impact of photoreceptors and RPE in various pathological conditions involving the retina, the precise mechanisms leading to neurodegeneration and death of retinal neurons are far from being fully elucidated. Likewise, the underlying mechanisms of neuroprotection are also still obscure. With the advent of next-generation sequencing, tremendous progress has been made in discovering genes and genetic defects that cause inherited RDDs. The major challenge now is to functionally characterize these gene products to delineate the biological mechanisms of retinal disease pathogenesis using in vitro and in vivo models, with the goal of designing gene-based treatments. Although much effort is directed towards identifying the genetic components of retinal disease, little is known about the role of epigenetic mechanisms in the development of complex and multifactorial retinal diseases. Epigenetic changes (e.g., methylation, histone modifications, microRNA dysregulation) via the regulation of gene expression may play a crucial role in the development and/or progression of common retinal diseases and warrant systematic investigations. While advances have been made in elucidating the pathophysiological mechanisms underlying the genetic causes of retinal dystrophies, therapeutic approaches are now being explored to mitigate vision loss in such patients. It is crucial to establish animal models to elucidate retinal and photoreceptor biology in retinal diseases and in the development of novel gene-based and cell-based therapeutic modalities. There is an evolving interest in developing nutrient-based neuroprotective therapy in retinal diseases. Newer and improved therapeutic approaches will greatly enhance the quality of life of individuals living with these potentially blinding diseases and facilitate effective disease management.

Research topics of interest for this Special Issue include, but are not limited to:

  • Novel mechanisms regulating protein trafficking to the photoreceptor outer segments
  • Mistrafficking of phototransduction proteins in retinal cell death
  • Mechanisms in age-related macular degeneration
  • Mechanisms of secondary cone photoreceptor cell death
  • Exosomes in retinal degenerative diseases
  • Genetic and epigenetic mechanisms in retinal degenerative diseases
  • Mitochondrial dysregulation in retinal degenerative diseases
  • Nutrient based therapy in retinal degenerative diseases
  • Adeno-associated viral gene therapy for retinal degenerative diseases
  • Mechanisms influencing transport and delivery of vitamin A and carotenoids to the eye
  • Genomics, proteomics, and metabolomics of age-related macular degeneration
  • Attenuation of inherited retinal degeneration progression with gene-based technology

Dr. Glenn Lobo
Dr. Altaf A. Kondkar
Guest Editors

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Published Papers (3 papers)

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Research

16 pages, 3288 KiB  
Article
Role of Nuclear Factor of Activated T Cells (NFAT) Pathway in Regulating Autophagy and Inflammation in Retinal Pigment Epithelial Cells
by Hsuan-Yeh Pan, Ashley V. Ladd, Manas R. Biswal and Mallika Valapala
Int. J. Mol. Sci. 2021, 22(16), 8684; https://doi.org/10.3390/ijms22168684 - 12 Aug 2021
Cited by 5 | Viewed by 2885
Abstract
Nuclear factor of activated T cells (NFAT) family of transcription factors are substrates of calcineurin and play an important role in integrating Ca2+ signaling with a variety of cellular functions. Of the five NFAT proteins (NFAT1-5), NFAT1-4 are subject to dephosphorylation and [...] Read more.
Nuclear factor of activated T cells (NFAT) family of transcription factors are substrates of calcineurin and play an important role in integrating Ca2+ signaling with a variety of cellular functions. Of the five NFAT proteins (NFAT1-5), NFAT1-4 are subject to dephosphorylation and activation by calcineurin, a Ca2+-calmodulin-dependent phosphatase. Increased levels of intracellular Ca2+ activates calcineurin, which in turn dephosphorylates and promotes nuclear translocation of NFAT. We investigated the functions of NFAT proteins in the retinal pigment epithelial cells (RPE). Our results show that NFAT-mediated luciferase activity was induced upon treatment with the bacterial endotoxin, lipopolysaccharide (LPS) and treatment with the NFAT peptide inhibitor, MAGPHPVIVITGPHEE (VIVIT) decreased LPS-induced NFAT luciferase activity. LPS-induced activation of NFAT-regulated cytokines (IL-6 and IL-8) is inhibited by treatment of cells with VIVIT. We also investigated the effects of NFAT signaling on the autophagy pathway. Our results show that inhibition of NFAT with VIVIT in cells deprived of nutrients resulted in cytosolic retention of transcription Factor EB (TFEB), decreased expression of TFEB-regulated coordinated Lysosomal Expression and Regulation CLEAR network genes and decreased starvation-induced autophagy flux in the RPE cells. In summary, these studies suggest that the NFAT pathway plays an important role in the regulation of autophagy and inflammation in the RPE. Full article
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16 pages, 3599 KiB  
Article
Photoreceptor Compartment-Specific TULP1 Interactomes
by Lindsey A. Ebke, Satyabrata Sinha, Gayle J. T. Pauer and Stephanie A. Hagstrom
Int. J. Mol. Sci. 2021, 22(15), 8066; https://doi.org/10.3390/ijms22158066 - 28 Jul 2021
Cited by 4 | Viewed by 2564
Abstract
Photoreceptors are highly compartmentalized cells with large amounts of proteins synthesized in the inner segment (IS) and transported to the outer segment (OS) and synaptic terminal. Tulp1 is a photoreceptor-specific protein localized to the IS and synapse. In the absence of Tulp1, several [...] Read more.
Photoreceptors are highly compartmentalized cells with large amounts of proteins synthesized in the inner segment (IS) and transported to the outer segment (OS) and synaptic terminal. Tulp1 is a photoreceptor-specific protein localized to the IS and synapse. In the absence of Tulp1, several OS-specific proteins are mislocalized and synaptic vesicle recycling is impaired. To better understand the involvement of Tulp1 in protein trafficking, our approach in the current study was to physically isolate Tulp1-containing photoreceptor compartments by serial tangential sectioning of retinas and to identify compartment-specific Tulp1 binding partners by immunoprecipitation followed by liquid chromatography tandem mass spectrometry. Our results indicate that Tulp1 has two distinct interactomes. We report the identification of: (1) an IS-specific interaction between Tulp1 and the motor protein Kinesin family member 3a (Kif3a), (2) a synaptic-specific interaction between Tulp1 and the scaffold protein Ribeye, and (3) an interaction between Tulp1 and the cytoskeletal protein microtubule-associated protein 1B (MAP1B) in both compartments. Immunolocalization studies in the wild-type retina indicate that Tulp1 and its binding partners co-localize to their respective compartments. Our observations are compatible with Tulp1 functioning in protein trafficking in multiple photoreceptor compartments, likely as an adapter molecule linking vesicles to molecular motors and the cytoskeletal scaffold. Full article
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14 pages, 3455 KiB  
Article
Conditional Loss of the Exocyst Component Exoc5 in Retinal Pigment Epithelium (RPE) Results in RPE Dysfunction, Photoreceptor Cell Degeneration, and Decreased Visual Function
by Bärbel Rohrer, Manas R. Biswal, Elisabeth Obert, Yujing Dang, Yanhui Su, Xiaofeng Zuo, Ben Fogelgren, Altaf A. Kondkar, Glenn P. Lobo and Joshua H. Lipschutz
Int. J. Mol. Sci. 2021, 22(10), 5083; https://doi.org/10.3390/ijms22105083 - 11 May 2021
Cited by 5 | Viewed by 2467
Abstract
To characterize the mechanisms by which the highly conserved exocyst trafficking complex regulates eye physiology in zebrafish and mice, we focused on Exoc5 (also known as sec10), a central exocyst component. We analyzed both exoc5 zebrafish mutants and retinal pigmented epithelium (RPE)-specific [...] Read more.
To characterize the mechanisms by which the highly conserved exocyst trafficking complex regulates eye physiology in zebrafish and mice, we focused on Exoc5 (also known as sec10), a central exocyst component. We analyzed both exoc5 zebrafish mutants and retinal pigmented epithelium (RPE)-specific Exoc5 knockout mice. Exoc5 is present in both the non-pigmented epithelium of the ciliary body and in the RPE. In this study, we set out to establish an animal model to study the mechanisms underlying the ocular phenotype and to establish if loss of visual function is induced by postnatal RPE Exoc5-deficiency. Exoc5−/− zebrafish had smaller eyes, with decreased number of melanocytes in the RPE and shorter photoreceptor outer segments. At 3.5 days post-fertilization, loss of rod and cone opsins were observed in zebrafish exoc5 mutants. Mice with postnatal RPE-specific loss of Exoc5 showed retinal thinning associated with compromised visual function and loss of visual photoreceptor pigments. Abnormal levels of RPE65 together with a reduced c-wave amplitude indicate a dysfunctional RPE. The retinal phenotype in Exoc5−/− mice was present at 20 weeks, but was more pronounced at 27 weeks, indicating progressive disease phenotype. We previously showed that the exocyst is necessary for photoreceptor ciliogenesis and retinal development. Here, we report that exoc5 mutant zebrafish and mice with RPE-specific genetic ablation of Exoc5 develop abnormal RPE pigmentation, resulting in retinal cell dystrophy and loss of visual pigments associated with compromised vision. Together, these data suggest that exocyst-mediated signaling in the RPE is required for RPE structure and function, indirectly leading to photoreceptor degeneration. Full article
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