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15 pages, 3840 KiB

Open AccessArticle

R-Ras1 and R-Ras2 Expression in Anatomical Regions and Cell Types of the Central Nervous System

by Gonzalo Garcia-Martin, Miriam Sanz-Rodriguez, Berta Alcover-Sanchez, Marta P. Pereira, Francisco Wandosell and Beatriz Cubelos

Int. J. Mol. Sci. 2022, 23(2), 978; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020978 - 17 Jan 2022

Cited by 1 | Viewed by 2503

Abstract

Since the optic nerve is one of the most myelinated tracts in the central nervous system (CNS), many myelin diseases affect the visual system. In this sense, our laboratory has recently reported that the GTPases R-Ras1 and R-Ras2 are essential for oligodendrocyte survival [...] Read more.

Since the optic nerve is one of the most myelinated tracts in the central nervous system (CNS), many myelin diseases affect the visual system. In this sense, our laboratory has recently reported that the GTPases R-Ras1 and R-Ras2 are essential for oligodendrocyte survival and maturation. Hypomyelination produced by the absence of one or both proteins triggers axonal degeneration and loss of visual and motor function. However, little is known about R-Ras specificity and other possible roles that they could play in the CNS. In this work, we describe how a lack of R-Ras1 and/or R-Ras2 could not be compensated by increased expression of the closely related R-Ras3 or classical Ras. We further studied R-Ras1 and R-Ras2 expression within different CNS anatomical regions, finding that both were more abundant in less-myelinated regions, suggesting their expression in non-oligodendroglial cells. Finally, using confocal immunostaining colocalization, we report for the first time that R-Ras2 is specifically expressed in neurons. Neither microglia nor astrocytes expressed R-Ras1 or R-Ras2. These results open a new avenue for the study of neuronal R-Ras2’s contribution to the process of myelination. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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22 pages, 4089 KiB

Open AccessArticle

Visual Disfunction due to the Selective Effect of Glutamate Agonists on Retinal Cells

by Santiago Milla-Navarro, Ariadna Diaz-Tahoces, Isabel Ortuño-Lizarán, Eduardo Fernández, Nicolás Cuenca, Francisco Germain and Pedro de la Villa

Int. J. Mol. Sci. 2021, 22(12), 6245; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126245 - 10 Jun 2021

Cited by 9 | Viewed by 1885

Abstract

One of the causes of nervous system degeneration is an excess of glutamate released upon several diseases. Glutamate analogs, like N-methyl-DL-aspartate (NMDA) and kainic acid (KA), have been shown to induce experimental retinal neurotoxicity. Previous results have shown that NMDA/KA neurotoxicity induces significant [...] Read more.

One of the causes of nervous system degeneration is an excess of glutamate released upon several diseases. Glutamate analogs, like N-methyl-DL-aspartate (NMDA) and kainic acid (KA), have been shown to induce experimental retinal neurotoxicity. Previous results have shown that NMDA/KA neurotoxicity induces significant changes in the full field electroretinogram response, a thinning on the inner retinal layers, and retinal ganglion cell death. However, not all types of retinal neurons experience the same degree of injury in response to the excitotoxic stimulus. The goal of the present work is to address the effect of intraocular injection of different doses of NMDA/KA on the structure and function of several types of retinal cells and their functionality. To globally analyze the effect of glutamate receptor activation in the retina after the intraocular injection of excitotoxic agents, a combination of histological, electrophysiological, and functional tools has been employed to assess the changes in the retinal structure and function. Retinal excitotoxicity caused by the intraocular injection of a mixture of NMDA/KA causes a harmful effect characterized by a great loss of bipolar, amacrine, and retinal ganglion cells, as well as the degeneration of the inner retina. This process leads to a loss of retinal cell functionality characterized by an impairment of light sensitivity and visual acuity, with a strong effect on the retinal OFF pathway. The structural and functional injury suffered by the retina suggests the importance of the glutamate receptors expressed by different types of retinal cells. The effect of glutamate agonists on the OFF pathway represents one of the main findings of the study, as the evaluation of the retinal lesions caused by excitotoxicity could be specifically explored using tests that evaluate the OFF pathway. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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21 pages, 3647 KiB

Open AccessArticle

Dexamethasone Downregulates Autophagy through Accelerated Turn-Over of the Ulk-1 Complex in a Trabecular Meshwork Cells Strain: Insights on Steroid-Induced Glaucoma Pathogenesis

by Diego Sbardella, Grazia Raffaella Tundo, Massimo Coletta, Gianluca Manni and Francesco Oddone

Int. J. Mol. Sci. 2021, 22(11), 5891; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115891 - 31 May 2021

Cited by 11 | Viewed by 2760

Abstract

Steroid-induced glaucoma is a severe pathological condition, sustained by a rapidly progressive increase in intraocular pressure (IOP), which is diagnosed in a subset of subjects who adhere to a glucocorticoid (GC)-based therapy. Molecular and clinical studies suggest that either natural or synthetic GCs [...] Read more.

Steroid-induced glaucoma is a severe pathological condition, sustained by a rapidly progressive increase in intraocular pressure (IOP), which is diagnosed in a subset of subjects who adhere to a glucocorticoid (GC)-based therapy. Molecular and clinical studies suggest that either natural or synthetic GCs induce a severe metabolic dysregulation of Trabecular Meshwork Cells (TMCs), an endothelial-derived histotype with phagocytic and secretive functions which lay at the iridocorneal angle in the anterior segment of the eye. Since TMCs physiologically regulate the composition and architecture of trabecular meshwork (TM), which is the main outflow pathway of aqueous humor, a fluid which shapes the eye globe and nourishes the lining cell types, GCs are supposed to trigger a pathological remodeling of the TM, inducing an IOP increase and retina mechanical compression. The metabolic dysregulation of TMCs induced by GCs exposure has never been characterized at the molecular detail. Herein, we report that, upon dexamethasone exposure, a TMCs strain develops a marked inhibition of the autophagosome biogenesis pathway through an enhanced turnover of two members of the Ulk-1 complex, the main platform for autophagy induction, through the Ubiquitin Proteasome System (UPS). Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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12 pages, 1956 KiB

Open AccessArticle

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

by Ulises Gómez-Pinedo, Yolanda García-Ávila, Lucía Gallego-Villarejo, Jordi A. Matías-Guiu, María Soledad Benito-Martín, Noelia Esteban-García, Inmaculada Sanclemente-Alamán, Vanesa Pytel, Lidia Moreno-Jiménez, Francisco Sancho-Bielsa, Lucía Vidorreta-Ballesteros, Paloma Montero-Escribano and Jorge Matías-Guiu

Int. J. Mol. Sci. 2021, 22(10), 5192; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105192 - 14 May 2021

Cited by 5 | Viewed by 1979

Abstract

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of [...] Read more.

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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20 pages, 9508 KiB

Open AccessArticle

Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography

by Rocío Benítez-Fernández, Carolina Melero-Jerez, Carmen Gil, Enrique J. de la Rosa, Ana Martínez and Fernando de Castro

Int. J. Mol. Sci. 2021, 22(5), 2440; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052440 - 28 Feb 2021

Cited by 4 | Viewed by 2762

Abstract

The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform [...] Read more.

The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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Review

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23 pages, 2585 KiB

Open AccessReview

Retinal Organoid Technology: Where Are We Now?

by Zuming Zhang, Zihui Xu, Fa Yuan, Kangxin Jin and Mengqing Xiang

Int. J. Mol. Sci. 2021, 22(19), 10244; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910244 - 23 Sep 2021

Cited by 17 | Viewed by 5940

Abstract

It is difficult to regenerate mammalian retinal cells once the adult retina is damaged, and current clinical approaches to retinal damages are very limited. The introduction of the retinal organoid technique empowers researchers to study the molecular mechanisms controlling retinal development, explore the [...] Read more.

It is difficult to regenerate mammalian retinal cells once the adult retina is damaged, and current clinical approaches to retinal damages are very limited. The introduction of the retinal organoid technique empowers researchers to study the molecular mechanisms controlling retinal development, explore the pathogenesis of retinal diseases, develop novel treatment options, and pursue cell/tissue transplantation under a certain genetic background. Here, we revisit the historical background of retinal organoid technology, categorize current methods of organoid induction, and outline the obstacles and potential solutions to next-generation retinal organoids. Meanwhile, we recapitulate recent research progress in cell/tissue transplantation to treat retinal diseases, and discuss the pros and cons of transplanting single-cell suspension versus retinal organoid sheet for cell therapies. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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48 pages, 10778 KiB

Open AccessReview

The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development

by Ellie L. Wagstaff, Andrea Heredero Berzal, Camiel J. F. Boon, Peter M. J. Quinn, Anneloor L. M. A. ten Asbroek and Arthur A. Bergen

Int. J. Mol. Sci. 2021, 22(13), 7081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137081 - 30 Jun 2021

Cited by 21 | Viewed by 4999

Abstract

Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use [...] Read more.

Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use of retinal organoids, researchers aim to manipulate these pathways to achieve better human representative models for retinal development and disease. To achieve this, a plethora of different small molecules and signaling factors have been used at various time points and concentrations in retinal organoid differentiations, with varying success. Additions differ from protocol to protocol, but their usefulness or efficiency has not yet been systematically reviewed. Interestingly, many of these small molecules affect the same and/or multiple pathways, leading to reduced reproducibility and high variability between studies. In this review, we make an inventory of the key signaling pathways involved in early retinogenesis and their effect on the development of the early retina in vitro. Further, we provide a comprehensive overview of the small molecules and signaling factors that are added to retinal organoid differentiation protocols, documenting the molecular and functional effects of these additions. Lastly, we comparatively evaluate several of these factors using our established retinal organoid methodology. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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25 pages, 2168 KiB

Open AccessReview

Retinal Stem Cell ‘Retirement Plans’: Growth, Regulation and Species Adaptations in the Retinal Ciliary Marginal Zone

by Amanda Miles and Vincent Tropepe

Int. J. Mol. Sci. 2021, 22(12), 6528; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126528 - 18 Jun 2021

Cited by 13 | Viewed by 3567

Abstract

The vertebrate retina develops from a specified group of precursor cells that adopt distinct identities and generate lineages of either the neural retina, retinal pigmented epithelium, or ciliary body. In some species, including teleost fish and amphibians, proliferative cells with stem-cell-like properties capable [...] Read more.

The vertebrate retina develops from a specified group of precursor cells that adopt distinct identities and generate lineages of either the neural retina, retinal pigmented epithelium, or ciliary body. In some species, including teleost fish and amphibians, proliferative cells with stem-cell-like properties capable of continuously supplying new retinal cells post-embryonically have been characterized and extensively studied. This region, termed the ciliary or circumferential marginal zone (CMZ), possibly represents a conserved retinal stem cell niche. In this review, we highlight the research characterizing similar CMZ-like regions, or stem-like cells located at the peripheral margin, across multiple different species. We discuss the proliferative parameters, multipotency and growth mechanisms of these cells to understand how they behave in vivo and how different molecular factors and signalling networks converge at the CMZ niche to regulate their activity. The evidence suggests that the mature retina may have a conserved propensity for homeostatic growth and plasticity and that dysfunction in the regulation of CMZ activity may partially account for dystrophic eye growth diseases such as myopia and hyperopia. A better understanding of the properties of CMZ cells will enable important insight into how an endogenous generative tissue compartment can adapt to altered retinal physiology and potentially even restore vision loss caused by retinal degenerative conditions. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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15 pages, 718 KiB

Open AccessReview

Advances in Regeneration of Retinal Ganglion Cells and Optic Nerves

by Fa Yuan, Mingwei Wang, Kangxin Jin and Mengqing Xiang

Int. J. Mol. Sci. 2021, 22(9), 4616; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094616 - 28 Apr 2021

Cited by 12 | Viewed by 4501

Abstract

Glaucoma, the second leading cause of blindness worldwide, is an incurable neurodegenerative disorder due to the dysfunction of retinal ganglion cells (RGCs). RGCs function as the only output neurons conveying the detected light information from the retina to the brain, which is a [...] Read more.

Glaucoma, the second leading cause of blindness worldwide, is an incurable neurodegenerative disorder due to the dysfunction of retinal ganglion cells (RGCs). RGCs function as the only output neurons conveying the detected light information from the retina to the brain, which is a bottleneck of vision formation. RGCs in mammals cannot regenerate if injured, and RGC subtypes differ dramatically in their ability to survive and regenerate after injury. Recently, novel RGC subtypes and markers have been uncovered in succession. Meanwhile, apart from great advances in RGC axon regeneration, some degree of experimental RGC regeneration has been achieved by the in vitro differentiation of embryonic stem cells and induced pluripotent stem cells or in vivo somatic cell reprogramming, which provides insights into the future therapy of myriad neurodegenerative disorders. Further approaches to the combination of different factors will be necessary to develop efficacious future therapeutic strategies to promote ultimate axon and RGC regeneration and functional vision recovery following injury. Full article

(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)

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