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Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment

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

Deadline for manuscript submissions: closed (15 March 2021) | Viewed by 19780

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Prof. Valeria Marigo

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Guest Editor

University of Modena and Reggio Emilia, Modena, Italy
Interests: retinitis pigmentosa; cell death mechanism; calcium; cGMP; neuroprotection

Special Issue Information

Dear Colleagues,

Degenerative diseases of the retina are characterized by the loss of photoreceptor cells and loss of vision. In the last thirty years, over 100 genes linked to inherited forms of these diseases have been identified, paving the way for multiple studies on the pathogenesis of these disorders. These studies underlined in retinal degeneration high genetic heterogeneity with autosomal dominant, recessive and X-linked inheritance, which hampers the development of a single treatment for such diseases. There have been extensive advances in our understanding of the mechanisms underlying photoreceptor demise. Some mechanisms are exclusive in specific forms of retinal degeneration but others appear to act as general responses in photoreceptors undergoing cell death. Studies on the identification of key molecules that can be targets for novel therapeutic intervention are under investigation. High enthusiasm arose with the first approval of an AAV-based gene therapy product for the treatment of LCA2 (Leber Congenital Amaurosis type 2), but such a specialized approach applies only to patients with recessive mutations in the RPE65 gene. Nevertheless, this recent success opened up new research topics for the development of novel biotechnological therapeutic molecules for inherited and non-inherited forms of retinal dystrophy based on either gene-specific or non-gene-specific approaches.

Contributions to this Special Issue should provide new insights into the pathogenesis of retinal degeneration, deepen our understanding of the molecular mechanisms activated in degenerating photoreceptors and discuss novel therapeutic opportunities based on gene supplementation therapy, RNA-based therapy and gene-independent neuroprotective approaches.

Prof. Valeria Marigo
Guest Editor

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Keywords

retinitis pigmentosa
Leber Congenital Amaurosis
Stargardt disease
photoreceptor
mutant protein
cell death
therapy

Published Papers (7 papers)

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Research

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17 pages, 3542 KiB

Open AccessArticle

Tlr2 Gene Deletion Delays Retinal Degeneration in Two Genetically Distinct Mouse Models of Retinitis Pigmentosa

by Alonso Sánchez-Cruz, Andrea C. Méndez, Ignacio Lizasoain, Pedro de la Villa, Enrique J. de la Rosa and Catalina Hernández-Sánchez

Int. J. Mol. Sci. 2021, 22(15), 7815; https://doi.org/10.3390/ijms22157815 - 22 Jul 2021

Cited by 8 | Viewed by 2143

Abstract

Although considered a rare retinal dystrophy, retinitis pigmentosa (RP) is the primary cause of hereditary blindness. Given its diverse genetic etiology (>3000 mutations in >60 genes), there is an urgent need for novel treatments that target common features of the disease. TLR2 is a key activator of innate immune response. To examine its role in RP progression we characterized the expression profile of Tlr2 and its adaptor molecules and the consequences of Tlr2 deletion in two genetically distinct models of RP: Pde6b^rd10/rd10 (rd10) and Rho^P23H/+ (P23H/+) mice. In both models, expression levels of Tlr2 and its adaptor molecules increased in parallel with those of the proinflammatory cytokine Il1b. In rd10 mice, deletion of a single Tlr2 allele had no effect on visual function, as evaluated by electroretinography. However, in both RP models, complete elimination of Tlr2 attenuated the loss of visual function and mitigated the loss of photoreceptor cell numbers. In Tlr2 null rd10 mice, we observed decreases in the total number of microglial cells, assessed by flow cytometry, and in the number of microglia infiltrating the photoreceptor layers. Together, these results point to TLR2 as a mutation-independent therapeutic target for RP. Full article

(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)

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12 pages, 1620 KiB

Open AccessArticle

New In Vitro Cellular Model for Molecular Studies of Retinitis Pigmentosa

by Li Huang, Meltem Kutluer, Elisa Adani, Antonella Comitato and Valeria Marigo

Int. J. Mol. Sci. 2021, 22(12), 6440; https://doi.org/10.3390/ijms22126440 - 16 Jun 2021

Cited by 5 | Viewed by 3242

Abstract

Retinitis pigmentosa (RP) is an inherited form of retinal degeneration characterized by primary rod photoreceptor cell death followed by cone loss. Mutations in several genes linked to the disease cause increased levels of cyclic guanosine monophosphate (cGMP) and calcium ion influxes. The purpose of this project was to develop a new in vitro photoreceptor degeneration model for molecular studies of RP. 661W cells were genetically modified to stably express the neural retina leucine zipper (NRL) transcription factor. One clone (661W-A11) was selected based on the expression of Nrl target genes. 661W-A11 showed a significant increase in expression of rod-specific genes but not of cone-specific genes, compared with 661W cells. Zaprinast was used to inhibit phosphodiesterase 6 (PDE6) activity to mimic photoreceptor degeneration in vitro. The activation of cell death pathways resulting from PDE6 inhibition was confirmed by detection of decreased viability and increased intracellular cGMP and calcium, as well as activation of protein kinase G (PKG) and calpains. In this new in vitro system, we validated the effects of previously published neuroprotective drugs. The 661W-A11 cells may serve as a new model for molecular studies of RP and for high-throughput drug screening. Full article

(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)

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12 pages, 1824 KiB

Open AccessArticle

Challenging Safety and Efficacy of Retinal Gene Therapies by Retinogenesis

by Elena Marrocco, Rosa Maritato, Salvatore Botta, Marianna Esposito and Enrico Maria Surace

Int. J. Mol. Sci. 2021, 22(11), 5767; https://doi.org/10.3390/ijms22115767 - 28 May 2021

Cited by 4 | Viewed by 2508

Abstract

Gene-expression programs modulated by transcription factors (TFs) mediate key developmental events. Here, we show that the synthetic transcriptional repressor (TR; ZF6-DB), designed to treat Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP), does not perturb murine retinal development, while maintaining its ability to block Rho expression transcriptionally. To express ZF6-DB into the developing retina, we pursued two approaches, (i) the retinal delivery (somatic expression) of ZF6-DB by Adeno-associated virus (AAV) vector (AAV-ZF6-DB) gene transfer during retinogenesis and (ii) the generation of a transgenic mouse (germ-line transmission, TR-ZF6-DB). Somatic and transgenic expression of ZF6-DB during retinogenesis does not affect retinal function of wild-type mice. The P347S mouse model of RHO-adRP, subretinally injected with AAV-ZF6-DB, or crossed with TR-ZF6-DB or shows retinal morphological and functional recovery. We propose the use of developmental transitions as an effective mode to challenge the safety of retinal gene therapies operating at genome, transcriptional, and transcript levels. Full article

(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)

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18 pages, 6691 KiB

Open AccessArticle

Retinal Pigment Epithelium Remodeling in Mouse Models of Retinitis Pigmentosa

by Debora Napoli, Martina Biagioni, Federico Billeri, Beatrice Di Marco, Noemi Orsini, Elena Novelli and Enrica Strettoi

Int. J. Mol. Sci. 2021, 22(10), 5381; https://doi.org/10.3390/ijms22105381 - 20 May 2021

Cited by 17 | Viewed by 3931

Abstract

In retinitis pigmentosa (RP), one of many possible genetic mutations causes rod degeneration, followed by cone secondary death leading to blindness. Accumulating evidence indicates that rod death triggers multiple, non-cell-autonomous processes, which include oxidative stress and inflammation/immune responses, all contributing to cone demise. Inflammation relies on local microglia and recruitment of immune cells, reaching the retina through breakdowns of the inner blood retinal barrier (iBRB). Leakage in the inner retina vasculature suggests similarly altered outer BRB, formed by junctions between retinal pigment epithelium (RPE) cells, which are crucial for retinal homeostasis, immune response, and privilege. We investigated the RPE structural integrity in three models of RP (rd9, rd10, and Tvrm4 mice) by immunostaining for zonula occludens-1 (ZO-1), an essential regulatory component of tight junctions. Quantitative image analysis demonstrated discontinuities in ZO-1 profiles in all mutants, despite different degrees of photoreceptor loss. ZO-1 interruption zones corresponded to leakage of in vivo administered, fluorescent dextran through the choroid-RPE interface, demonstrating barrier dysfunction. Dexamethasone, administered to rd10 mice for rescuing cones, also rescued RPE structure. Thus, previously undetected, stereotyped abnormalities occur in the RPE of RP mice; pharmacological targeting of inflammation supports a feedback loop leading to simultaneous protection of cones and the RPE. Full article

(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)

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20 pages, 4636 KiB

Open AccessArticle

Impaired Ca²⁺ Sensitivity of a Novel GCAP1 Variant Causes Cone Dystrophy and Leads to Abnormal Synaptic Transmission Between Photoreceptors and Bipolar Cells

by Valerio Marino, Giuditta Dal Cortivo, Paolo Enrico Maltese, Giorgio Placidi, Elisa De Siena, Benedetto Falsini, Matteo Bertelli and Daniele Dell’Orco

Int. J. Mol. Sci. 2021, 22(8), 4030; https://doi.org/10.3390/ijms22084030 - 14 Apr 2021

Cited by 4 | Viewed by 1753

Abstract

Guanylate cyclase-activating protein 1 (GCAP1) is involved in the shutdown of the phototransduction cascade by regulating the enzymatic activity of retinal guanylate cyclase via a Ca²⁺/cGMP negative feedback. While the phototransduction-associated role of GCAP1 in the photoreceptor outer segment is widely established, its implication in synaptic transmission to downstream neurons remains to be clarified. Here, we present clinical and biochemical data on a novel isolate GCAP1 variant leading to a double amino acid substitution (p.N104K and p.G105R) and associated with cone dystrophy (COD) with an unusual phenotype. Severe alterations of the electroretinogram were observed under both scotopic and photopic conditions, with a negative pattern and abnormally attenuated b-wave component. The biochemical and biophysical analysis of the heterologously expressed N104K-G105R variant corroborated by molecular dynamics simulations highlighted a severely compromised Ca²⁺-sensitivity, accompanied by minor structural and stability alterations. Such differences reflected on the dysregulation of both guanylate cyclase isoforms (RetGC1 and RetGC2), resulting in the constitutive activation of both enzymes at physiological levels of Ca²⁺. As observed with other GCAP1-associated COD, perturbation of the homeostasis of Ca²⁺ and cGMP may lead to the toxic accumulation of second messengers, ultimately triggering cell death. However, the abnormal electroretinogram recorded in this patient also suggested that the dysregulation of the GCAP1–cyclase complex further propagates to the synaptic terminal, thereby altering the ON-pathway related to the b-wave generation. In conclusion, the pathological phenotype may rise from a combination of second messengers’ accumulation and dysfunctional synaptic communication with bipolar cells, whose molecular mechanisms remain to be clarified. Full article

(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)

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Review

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14 pages, 641 KiB

Open AccessReview

Delivery Systems of Retinoprotective Proteins in the Retina

by Ivan T. Rebustini, Alexandra Bernardo-Colón, Alejandra Isasi Nalvarte and S. Patricia Becerra

Int. J. Mol. Sci. 2021, 22(10), 5344; https://doi.org/10.3390/ijms22105344 - 19 May 2021

Cited by 4 | Viewed by 2298

Abstract

Retinoprotective proteins play important roles for retinal tissue integrity. They can directly affect the function and the survival of photoreceptors, and/or indirectly target the retinal pigment epithelium (RPE) and endothelial cells that support these tissues. Retinoprotective proteins are used in basic, translational and in clinical studies to prevent and treat human retinal degenerative disorders. In this review, we provide an overview of proteins that protect the retina and focus on pigment epithelium-derived factor (PEDF), and its effects on photoreceptors, RPE cells, and endothelial cells. We also discuss delivery systems such as pharmacologic and genetic administration of proteins to achieve photoreceptor survival and retinal tissue integrity. Full article

(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)

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23 pages, 13522 KiB

Open AccessReview

Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity

by Yannick Das, Daniëlle Swinkels and Myriam Baes

Int. J. Mol. Sci. 2021, 22(8), 4101; https://doi.org/10.3390/ijms22084101 - 15 Apr 2021

Cited by 11 | Viewed by 2667

Abstract

Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases caused by peroxisomal dysfunction. Importantly, most patients suffering from peroxisomal biogenesis disorders, even those with a milder disease course, present with a number of ocular symptoms, including retinopathy. Patients with a selective defect in either peroxisomal α- or β-oxidation or ether lipid synthesis also suffer from vision problems. In this review, we thoroughly discuss the ophthalmological pathology in peroxisomal disorder patients and, where possible, the corresponding animal models, with a special emphasis on the retina. In addition, we attempt to link the observed retinal phenotype to the underlying biochemical alterations. It appears that the retinal pathology is highly variable and the lack of histopathological descriptions in patients hampers the translation of the findings in the mouse models. Furthermore, it becomes clear that there are still large gaps in the current knowledge on the contribution of the different metabolic disturbances to the retinopathy, but branched chain fatty acid accumulation and impaired retinal PUFA homeostasis are likely important factors. Full article

(This article belongs to the Special Issue Retinal Degeneration: Molecular Mechanism, Pathogenesis and Treatment)

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