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Biomolecules
Special Issues
Molecular and Cellular Mechanisms of Optic Neuropathies
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Molecular and Cellular Mechanisms of Optic Neuropathies

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 9761

Special Issue Editor

Dr. Oliver W. Gramlich

E-Mail Website
Guest Editor
Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA
Interests: optic neuropathies; demyelinating disorders; glaucoma; neuromyelitis optica; multiple sclerosis

Special Issue Information

Dear Colleagues,

Optic Neuropathy describes a diverse group of diseases that cause vision loss and blindness due to the degeneration of Retinal Ganglion Cells (RGC), the neurons that transduce visual information from the retina to the brain via the optic nerve. The individual pathobiology of RGC and optic nerve axon degeneration is usually multifactorial and differs significantly across optic neuropathies such as Glaucoma, Multiple Sclerosis, and Leber's optic neuropathy. As society continues to age, more and more people will be affected by these diseases, thereby causing an enormous socioeconomic burden. Hence, reliable in vitro and in vivo models are needed to advance our understanding of disease pathophysiology and to accelerate the development of new treatments.

This Special Issue emphasizes but is not limited to, glaucomatous, ischemic, mitochondrial, and autoimmune-mediated optic neuropathies. It aims to summarize current knowledge in pathologies and new discoveries of innovative treatments. Most of these data were obtained using animal models and the next important step is to apply this knowledge to treatment in humans.

Dr. Oliver W. Gramlich
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • optic neuropathies
  • cellular and molecular mechanisms of RGCs and/or axonal damage and repair
  • optic nerve regeneration

Published Papers (4 papers)

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Research

19 pages, 3087 KiB  
Article
Heat Shock Protein Upregulation Supplemental to Complex mRNA Alterations in Autoimmune Glaucoma
by Sabrina Reinehr, Armin Safaei, Pia Grotegut, Annika Guntermann, Teresa Tsai, Stephan A. Hahn, Steffen Kösters, Carsten Theiss, Katrin Marcus, H. Burkhard Dick, Caroline May and Stephanie C. Joachim
Biomolecules 2022, 12(10), 1538; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12101538 - 21 Oct 2022
Cited by 2 | Viewed by 1933
Abstract
Glaucomatous optic neuropathy is a common cause for blindness. An elevated intraocular pressure is the main risk factor, but also a contribution of the immune system seems likely. In the experimental autoimmune glaucoma model used here, systemic immunization with an optic nerve homogenate [...] Read more.
Glaucomatous optic neuropathy is a common cause for blindness. An elevated intraocular pressure is the main risk factor, but also a contribution of the immune system seems likely. In the experimental autoimmune glaucoma model used here, systemic immunization with an optic nerve homogenate antigen (ONA) leads to retinal ganglion cell (RGC) and optic nerve degeneration. We processed retinae for quantitative real-time PCR and immunohistology 28 days after immunization. Furthermore, we performed mRNA profiling in this model for the first time. We detected a significant RGC loss in the ONA retinae. This was accompanied by an upregulation of mRNA expression of genes belonging to the heat shock protein family. Furthermore, mRNA expression levels of the genes of the immune system, such as C1qa, C1qb, Il18, and Nfkb1, were upregulated in ONA animals. After laser microdissection, inner retinal layers were used for mRNA microarrays. Nine of these probes were significantly upregulated in ONA animals (p < 0.05), including Hba-a1 and Cxcl10, while fifteen probes were significantly downregulated in ONA animals (p < 0.05), such as Gdf15 and Wwox. Taken together, these findings provide further insights into the pivotal role of the immune response in glaucomatous optic neuropathy and could help to identify novel diagnostic or therapeutic strategies. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Optic Neuropathies)
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16 pages, 2744 KiB  
Article
Targeting Cholesterol Homeostasis Improves Recovery in Experimental Optic Neuritis
by Cheyanne R. Godwin, Jeffrey J. Anders, Lin Cheng, Benjamin W. Elwood, Randy H. Kardon and Oliver W. Gramlich
Biomolecules 2022, 12(10), 1437; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12101437 - 07 Oct 2022
Cited by 2 | Viewed by 1980
Abstract
Acute optic neuritis (ON) is a common cause of vision loss and is often associated with multiple sclerosis (MS). Cholesterol recycling has been identified as a key limiting factor in recovery after demyelination events. Thus, the purpose of our study was to determine [...] Read more.
Acute optic neuritis (ON) is a common cause of vision loss and is often associated with multiple sclerosis (MS). Cholesterol recycling has been identified as a key limiting factor in recovery after demyelination events. Thus, the purpose of our study was to determine if the augmentation of cholesterol transport by gentisic acid (GA) benefits retinal ganglion cell (RGC) development and myelination in organoid systems and enables the recovery of the ocular phenotype upon systemic GA treatment in a MOG-induced experimental autoimmune encephalomyelitis (EAE) ON model. The retinal organoids treated with GA demonstrate an accelerated maturation when compared to the conventionally derived organoids, which was evidenced by the improved organization of Brn3a-GFP+RGC and increased synaptogenesis. A GA supplementation in brain organoids leads to a 10-fold increase in NG2 and Olig2 expression. Weekly GA injections of EAE mice significantly lessened motor-sensory impairment, protected amplitudes in pattern electroretinogram recordings, and preserved visual acuity over the study period of 56 days. Furthermore, GA-treated EAE mice revealed diminished GCL/IPL complex thinning when compared to the untreated EAE mice. An optic nerve histopathology revealed less severe grades of demyelination in the GA-treated EAE cohort and fewer infiltrating cells were observed. Interventions to improve cholesterol homeostasis may be a viable approach to promoting the rehabilitation of MS patients. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Optic Neuropathies)
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16 pages, 3725 KiB  
Article
Selective Upregulation of SIRT1 Expression in Retinal Ganglion Cells by AAV-Mediated Gene Delivery Increases Neuronal Cell Survival and Alleviates Axon Demyelination Associated with Optic Neuritis
by Ahmara G. Ross, Brahim Chaqour, Devin S. McDougald, Kimberly E. Dine, Thu T. Duong, Ryan E. Shindler, Jipeng Yue, Tehui Liu and Kenneth S. Shindler
Biomolecules 2022, 12(6), 830; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060830 - 14 Jun 2022
Cited by 11 | Viewed by 2941
Abstract
Optic neuritis (ON), the most common ocular manifestation of multiple sclerosis, is an autoimmune inflammatory demyelinating disease also characterized by degeneration of retinal ganglion cells (RGCs) and their axons, which commonly leads to visual impairment despite attempted treatments. Although ON disease etiology is [...] Read more.
Optic neuritis (ON), the most common ocular manifestation of multiple sclerosis, is an autoimmune inflammatory demyelinating disease also characterized by degeneration of retinal ganglion cells (RGCs) and their axons, which commonly leads to visual impairment despite attempted treatments. Although ON disease etiology is not known, changes in the redox system and exacerbated optic nerve inflammation play a major role in the pathogenesis of the disease. Silent information regulator 1 (sirtuin-1/SIRT1) is a ubiquitously expressed NAD+-dependent deacetylase, which functions to reduce/prevent both oxidative stress and inflammation in various tissues. Non-specific upregulation of SIRT1 by pharmacologic and genetic approaches attenuates RGC loss in experimental ON. Herein, we hypothesized that targeted expression of SIRT1 selectively in RGCs using an adeno-associated virus (AAV) vector as a delivery vehicle is an effective approach to reducing neurodegeneration and preserving vision in ON. We tested this hypothesis through intravitreal injection of AAV7m8.SNCG.SIRT1, an AAV2-derived vector optimized for highly efficient SIRT1 transgene transfer and protein expression into RGCs in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis that recapitulates optic neuritis RGC loss and axon demyelination. Our data show that EAE mice injected with a control vehicle exhibit progressive alteration of visual function reflected by decreasing optokinetic response (OKR) scores, whereas comparatively, AAV7m8.SNCG.SIRT1-injected EAE mice maintain higher OKR scores, suggesting that SIRT1 reduces the visual deficit imparted by EAE. Consistent with this, RGC survival determined by immunolabeling is increased and axon demyelination is decreased in the AAV7m8.SNCG.SIRT1 RGC-injected group of EAE mice compared to the mouse EAE counterpart injected with a vehicle or with control vector AAV7m8.SNCG.eGFP. However, immune cell infiltration of the optic nerve is not significantly different among all EAE groups of mice injected with either vehicle or AAV7m8.SNCG.SIRT1. We conclude that despite minimally affecting the inflammatory response in the optic nerve, AAV7m8-mediated SIRT1 transfer into RGCs has a neuroprotective potential against RGC loss, axon demyelination and vison deficits associated with EAE. Together, these data suggest that SIRT1 exerts direct effects on RGC survival and function. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Optic Neuropathies)
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11 pages, 2870 KiB  
Article
Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models
by Huilan Zeng, Alina V. Dumitrescu, David Wadkins, Benjamin W. Elwood, Oliver W. Gramlich and Markus H. Kuehn
Biomolecules 2022, 12(2), 281; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12020281 - 09 Feb 2022
Cited by 5 | Viewed by 2394
Abstract
Neuroinflammation significantly contributes to the pathophysiology of several neurodegenerative diseases. This is also the case in glaucoma and may be a reason why many patients suffer from progressive vision loss despite maximal reduction in intraocular pressure. Pioglitazone is an agonist of the peroxisome [...] Read more.
Neuroinflammation significantly contributes to the pathophysiology of several neurodegenerative diseases. This is also the case in glaucoma and may be a reason why many patients suffer from progressive vision loss despite maximal reduction in intraocular pressure. Pioglitazone is an agonist of the peroxisome proliferator-activated receptor gamma (PPARγ) whose pleiotrophic activities include modulation of cellular energy metabolism and reduction in inflammation. In this study we employed the DBA2/J mouse model of glaucoma with chronically elevated intraocular pressure to investigate whether oral low-dose pioglitazone treatment preserves retinal ganglion cell (RGC) survival. We then used an inducible glaucoma model in C57BL/6J mice to determine visual function, pattern electroretinographs, and tracking of optokinetic reflex. Our findings demonstrate that pioglitazone treatment does significantly protect RGCs and prevents axonal degeneration in the glaucomatous retina. Furthermore, treatment preserves and partially reverses vision loss in spite of continuously elevated intraocular pressure. These data suggest that pioglitazone may provide treatment benefits for those glaucoma patients experiencing continued vision loss. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Optic Neuropathies)
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