Animal Models of Exfoliation Syndrome, Now and Future

John, Simon W. M.; Harder, Jeffrey M.; Fingert, John H.; Anderson, Michael G.

doi:10.1097/ijg.0000000000000121

Cited by 12 publications

(6 citation statements)

References 52 publications

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“…Pseudoexfoliation glaucoma (PXG) is a subset of POAG in which a systemic age-related elastinopathy (pseudoexfoliation syndrome) presents with ocular manifestations featuring fibrillar deposition in anterior segment structures, including trabecular meshwork. [119][120][121][122][123] Patients with PXG harbor primary tenon fibroblast cells (isolated from trabecular meshwork) with mitochondrial dysfunction, as well as a dysregulated lysosome-autophagosome formation compared to agematched POAG control cells. 124 This results in a reduction of autophagy events and may explain both the greater presence of dysfunctional mitochondria in the cells (reduced mitophagy) and an accumulation of material in the extracellular matrix (cellular aggregopathy) compared to POAG cells.…”

Section: Glaucomatous Optic Neuropathymentioning

confidence: 99%

Mitophagy: An Emerging Target in Ocular Pathology

Skeie

Nishimura

Wang

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Mitochondrial function is essential for the viability of aerobic eukaryotic cells, as mitochondria provide energy through the generation of adenosine triphosphate (ATP), regulate cellular metabolism, provide redox balancing, participate in immune signaling, and can initiate apoptosis. Mitochondria are dynamic organelles that participate in a cyclical and ongoing process of regeneration and autophagy (clearance), termed mitophagy specifically for mitochondrial (macro)autophagy. An imbalance in mitochondrial function toward mitochondrial dysfunction can be catastrophic for cells and has been characterized in several common ophthalmic diseases. In this article, we review mitochondrial homeostasis in detail, focusing on the balance of mitochondrial dynamics including the processes of fission and fusion, and provide a description of the mechanisms involved in mitophagy. Furthermore, this article reviews investigations of ocular diseases with impaired mitophagy, including Fuchs endothelial corneal dystrophy, primary open-angle glaucoma, diabetic retinopathy, and age-related macular degeneration, as well as several primary mitochondrial diseases with ocular phenotypes that display impaired mitophagy, including mitochondrial encephalopathy lactic acidosis stroke, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia. The results of various studies using cell culture, animal, and human tissue models are presented and reflect a growing awareness of mitophagy impairment as an important feature of ophthalmic disease pathology. As this review indicates, it is imperative that mitophagy be investigated as a targetable mechanism in developing therapies for ocular diseases characterized by oxidative stress and mitochondrial dysfunction.

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Section: Glaucomatous Optic Neuropathymentioning

confidence: 99%

Mitophagy: An Emerging Target in Ocular Pathology

Skeie

Nishimura

Wang

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…The formation of an XFM-like material has been reported in two potential animal models, porcine and mice (reviewed in 12 ). The porcine model developed the material after induction of cataracts with a high sucrose diet and the material was shown to contain crystallins.…”

Section: Introductionmentioning

confidence: 99%

Growth Factors, Oxidative Damage, and Inflammation in Exfoliation Syndrome

Borrás¹

2018

Journal of Glaucoma

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Exfoliation syndrome (XFS) produces deleterious ocular aging and has protean systemic manifestations. Local ocular production of TGFβ1 is of central importance in XFS. TGFβ1 appears to induce the expression of LOXL1 and the production of other extracellular matrix components which are known to be present in exfoliation material. Furthermore, results from several studies find that the aqueous humor of exfoliation glaucoma patients exhibits a decreased antioxidant defense and increased oxidative stress systems. Finally, studies show that the levels of interleukin-6 and interleukin-8 in the aqueous humor of XFS patients were 3-fold higher than in controls. Overall TGFβ1, as well as a prooxidative and proinflammatory environment seems to play an important role in XFS.

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“…(1,2), and is characterized by optic nerve cupping (thinning of the neuroretinal rim at the optic nerve head) and progressive optic nerve and retinal ganglion cell (RGC) degeneration as well as functional deficit revealed by psychophysical tests (3,4). Although factors causing the eventual RGC death and blindness remain controversial (1,(5)(6)(7)(8), increasing evidence from human patients and animal models has shown that the disease is associated with an early mild diffuse loss of retinal sensitivity or inner retinal response decrease (9)(10)(11)(12)(13)(14). Although it is unclear whether these functional changes are a prelude or even causal to RGC death and blindness, elucidating the underlying synaptic and cellular mechanisms for such sensitivity/response decline will nevertheless provide novel insights pertaining to early detection and treatment of human glaucoma.…”

mentioning

confidence: 99%

Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

Pang

Frankfort

Gross

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3-7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.laucoma is a leading cause of irreversible blindness in the United States and the world (1, 2), and is characterized by optic nerve cupping (thinning of the neuroretinal rim at the optic nerve head) and progressive optic nerve and retinal ganglion cell (RGC) degeneration as well as functional deficit revealed by psychophysical tests (3, 4). Although factors causing the eventual RGC death and blindness remain controversial (1, 5-8), increasing evidence from human patients and animal models has shown that the disease is associated with an early mild diffuse loss of retinal sensitivity or inner retinal response decrease (9-14). Although it is unclear whether these functional changes are a prelude or even causal to RGC death and blindness, elucidating the underlying synaptic and cellular mechanisms for such sensitivity/response decline will nevertheless provide novel insights pertaining to early detection and treatment of human glaucoma.Multiple risk factors are associated with glaucomatous diseases, among which elevated intraocular pressure (IOP) is widely accepted as the most significant for both disease onset and progression (2, 15). Because high IOP (H-IOP) is an important risk factor, many experimental animal models of elevated IOP have been developed in multiple species including monkeys, rats, and mice (16)(17)(18)(19)(20)(21)(22). Most experiments performed in animal models have focused on anatomical and histopathological analyses of RGC death, axon loss, and changes to axonal projections ...

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Animal Models of Exfoliation Syndrome, Now and Future

Cited by 12 publications

References 52 publications

Mitophagy: An Emerging Target in Ocular Pathology

Mitophagy: An Emerging Target in Ocular Pathology

Growth Factors, Oxidative Damage, and Inflammation in Exfoliation Syndrome

Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice

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