scholarly journals DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Olivia J. Marola ◽  
Stephanie B. Syc-Mazurek ◽  
Richard T. Libby
Keyword(s):  
Optic Nerve ◽  
Ocular Hypertension ◽  
Optic Nerve Head ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Axonal Degeneration ◽  
Axonal Injury ◽  
Retinal Ganglion ◽  
Age Related

Abstract Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been implicated as drivers of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 after glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas, but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration.

scholarly journals DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice

2019 ◽  
Author(s):  
Olivia J. Marola ◽  
Stephanie B. Syc-Mazurek ◽  
Richard T. Libby
Keyword(s):  
Optic Nerve ◽  
Ocular Hypertension ◽  
Optic Nerve Head ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Axonal Degeneration ◽  
Axonal Injury ◽  
Retinal Ganglion ◽  
Age Related

AbstractGlaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) has been implicated as a driver of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 upon glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration.

scholarly journals A Methodology for Individual-Specific Modeling of Rat Optic Nerve Head Biomechanics in Glaucoma

2018 ◽  
Vol 140 (8) ◽  
Author(s):  
Stephen A. Schwaner ◽  
Alison M. Kight ◽  
Robert N. Perry ◽  
Marta Pazos ◽  
Hongli Yang ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Optic Nerve Head ◽  
Cellular Response ◽  
Ganglion Cells ◽  
Axonal Injury ◽  
Retinal Ganglion ◽  
Mechanistic Studies ◽  
Specific Modeling ◽  
Initial Results ◽  
Model Strain

Glaucoma is the leading cause of irreversible blindness and involves the death of retinal ganglion cells (RGCs). Although biomechanics likely contributes to axonal injury within the optic nerve head (ONH), leading to RGC death, the pathways by which this occurs are not well understood. While rat models of glaucoma are well-suited for mechanistic studies, the anatomy of the rat ONH is different from the human, and the resulting differences in biomechanics have not been characterized. The aim of this study is to describe a methodology for building individual-specific finite element (FE) models of rat ONHs. This method was used to build three rat ONH FE models and compute the biomechanical environment within these ONHs. Initial results show that rat ONH strains are larger and more asymmetric than those seen in human ONH modeling studies. This method provides a framework for building additional models of normotensive and glaucomatous rat ONHs. Comparing model strain patterns with patterns of cellular response seen in studies using rat glaucoma models will help us to learn more about the link between biomechanics and glaucomatous cell death, which in turn may drive the development of novel therapies for glaucoma.

Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

2019 ◽  
Vol 25 (28) ◽  
pp. 3057-3073 ◽  
Author(s):  
Kobra B. Juybari ◽  
Azam Hosseinzadeh ◽  
Habib Ghaznavi ◽  
Mahboobeh Kamali ◽  
Ahad Sedaghat ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Ganglion Cells ◽  
Axon Growth ◽  
Nerve Fibers ◽  
Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

scholarly journals Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

2020 ◽  
Author(s):  
Niccolo’ Tesi ◽  
Sven J van der Lee ◽  
Marc Hulsman ◽  
Iris E Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Older Adults ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Risk Scores ◽  
Human Longevity ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

scholarly journals Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Olivia J. Marola ◽  
Stephanie B. Syc-Mazurek ◽  
Gareth R. Howell ◽  
Richard T. Libby
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Retinal Vessel ◽  
Vessel Diameter ◽  
Retinal Ganglion ◽  
Retinal Ganglion Cell Death ◽  
Ganglion Cell Death

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

scholarly journals The role of nitric oxide and endothelin on optic nerve head blood flow autoregulation

2012 ◽  
Vol 13 (Suppl 1) ◽  
pp. A28
Author(s):  
Doreen Schmidl ◽  
Agnes Boltz ◽  
Semira Kaya ◽  
René Werkmeister ◽  
Reinhard Told ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Optic Nerve ◽  
Optic Nerve Head

Parapapillary atrophy in optic neuropathies: Histology and clinical relevance

2021 ◽  
pp. 112067212110606
Author(s):  
Ana Banc ◽  
Stefania Bianchi Marzoli
Keyword(s):  
Optic Nerve ◽  
Optic Neuropathy ◽  
Optic Nerve Head ◽  
Clinical Findings ◽  
Age Related Macular Degeneration ◽  
Glaucomatous Optic Neuropathy ◽  
Age Related ◽  
High Resolution Images ◽  
Parapapillary Atrophy ◽  
Optic Nerve Disorders

Parapapillary atrophy is one of the parameters of the optic nerve head area which are assessed during the ophthalmoscopic examination particularly useful to characterize glaucomatous optic neuropathy. Optical coherence tomography evaluation provides high-resolution images of the optic nerve head and surrounding area, and can be used to study parapapillary atrophy. Different parapapillary atrophy zones were described depending on their histological features and research has been conducted to investigate the possible association between the presence and/ or size of parapapillary atrophy zones and several optic nerve disorders. In this review we discuss the histology and the clinical findings related to parapapillary atrophy in patients with glaucomatous optic neuropathy, non-glaucomatous optic neuropathies (e.g. arteritic and non-arteritic anterior ischemic optic neuropathies; suprasellar and parasellar tumors), and other ocular conditions (e.g. high myopia; age-related macular degeneration). Two different histologic classifications were identified. Parapapillary atrophy was demonstrated in glaucoma and glaucoma-like neuropathies, but not in other types of optic nerve disorders.

scholarly journals Microvascular Density Is Associated With Retinal Ganglion Cell Axonal Volume in the Laminar Compartments of the Human Optic Nerve Head

2018 ◽  
Vol 59 (3) ◽  
pp. 1562 ◽  
Author(s):  
Min H. Kang ◽  
Mengchen Suo ◽  
Chandrakumar Balaratnasingam ◽  
Paula K. Yu ◽  
William H. Morgan ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Optic Nerve Head ◽  
Microvascular Density ◽  
Retinal Ganglion ◽  
Human Optic Nerve
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