The Telomerase Reverse Transcriptase (TERT) and p53 Regulate Mammalian PNS and CNS Axon Regeneration downstream of c-Myc

SummaryAlthough several genes have been identified to promote axon regeneration in the central nervous system, our understanding of the molecular mechanisms by which mammalian axon regeneration is regulated is still limited and fragmented. Here by using sensory axon and optic nerve regeneration as model systems, we revealed an unexpected role of telomerase reverse transcriptase (TERT) in regulation of axon regeneration. We also provided strong evidence that TERT and p53 acted downstream of c-Myc to control sensory axon regeneration. More importantly, overexpression of p53 in sensory neurons and retinal ganglion cells (RGCs) was sufficient to promote sensory axon and optic never regeneration, respectively. The study revealed a novel c-Myc-TERT-p53 signaling pathway, expanding horizons for novel approaches promoting CNS axon regeneration.

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Harnessing Astrocytes and Müller Glial Cells in the Retina for Survival and Regeneration of Retinal Ganglion Cells

Cells ◽

10.3390/cells10061339 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1339

Author(s):

Hyung-Suk Yoo ◽

Ushananthini Shanmugalingam ◽

Patrice D. Smith

Keyword(s):

Spinal Cord ◽

Optic Nerve ◽

Retinal Ganglion Cells ◽

Axon Regeneration ◽

Ganglion Cells ◽

Reactive Gliosis ◽

Retinal Ganglion ◽

Cord Injury ◽

The Central Nervous System ◽

Retinal Degenerative Diseases

Astrocytes have been associated with the failure of axon regeneration in the central nervous system (CNS), as it undergoes reactive gliosis in response to damages to the CNS and functions as a chemical and physical barrier to axon regeneration. However, beneficial roles of astrocytes have been extensively studied in the spinal cord over the years, and a growing body of evidence now suggests that inducing astrocytes to become more growth-supportive can promote axon regeneration after spinal cord injury (SCI). In retina, astrocytes and Müller cells are known to undergo reactive gliosis after damage to retina and/or optic nerve and are hypothesized to be either detrimental or beneficial to survival and axon regeneration of retinal ganglion cells (RGCs). Whether they can be induced to become more growth-supportive after retinal and optic nerve injury has yet to be determined. In this review, we pinpoint the potential molecular pathways involved in the induction of growth-supportive astrocytes in the spinal cord and suggest that stimulating the activation of these pathways in the retina could represent a new therapeutic approach to promoting survival and axon regeneration of RGCs in retinal degenerative diseases.

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

Current Pharmaceutical Design ◽

10.2174/1381612825666190829151314 ◽

2019 ◽

Vol 25 (28) ◽

pp. 3057-3073 ◽

Cited By ~ 6

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.

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

Cell Death and Disease ◽

10.1038/s41419-020-02990-0 ◽

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.

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Cytotoxic and anti-excitotoxic effects of selected plant and algal extracts using COMET and cell viability assays

Scientific Reports ◽

10.1038/s41598-021-88089-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Abeer Aldbass ◽

Musarat Amina ◽

Nawal M. Al Musayeib ◽

Ramesa Shafi Bhat ◽

Sara Al-Rashed ◽

...

Keyword(s):

Cell Viability ◽

Plant Extracts ◽

Ganglion Cells ◽

Cell Damage ◽

Primary Cultures ◽

Glutamate Excitotoxicity ◽

Retinal Ganglion ◽

Gradual Loss ◽

The Central Nervous System ◽

Mtt Assays

AbstractExcess glutamate in the central nervous system may be a major cause of neurodegenerative diseases with gradual loss and dysfunction of neurons. Primary or secondary metabolites from medicinal plants and algae show potential for treatment of glutamate-induced excitotoxicity. Three plant extracts were evaluated for impact on glutamate excitotoxicity-induced in primary cultures of retinal ganglion cells (RGC). These cells were treated separately in seven groups: control; Plicosepalus. curviflorus treated; Saussurea lappa treated; Cladophora glomerate treated. Cells were treated independently with 5, 10, 50, or 100 µg/ml of extracts of plant or alga material, respectively, for 2 h. Glutamate-treated cells (48 h with 5, 10, 50, or 100 µM glutamate); and P. curviflorus/glutamate; S. lappa/glutamate; C. glomerata/glutamate [pretreatment with extract for 2 h (50 and 100 µg/ml) before glutamate treatment with 100 µM for 48 h]. Comet and MTT assays were used to assess cell damage and cell viability. The number of viable cells fell significantly after glutamate exposure. Exposure to plant extracts caused no notable effect of viability. All tested plants extracts showed a protective effect against glutamate excitotoxicity-induced RGC death. Use of these extracts for neurological conditions related to excitotoxicity and oxidative stress might prove beneficial.

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Bipolar cell pathways for color vision in non-primate dichromats

Visual Neuroscience ◽

10.1017/s0952523810000271 ◽

2010 ◽

Vol 28 (1) ◽

pp. 51-60 ◽

Cited By ~ 26

Author(s):

CHRISTIAN PULLER ◽

SILKE HAVERKAMP

Keyword(s):

Color Vision ◽

Bipolar Cell ◽

Ganglion Cells ◽

Color Discrimination ◽

Model Systems ◽

Retinal Ganglion ◽

Retinal Pathways ◽

Retinal Information Processing ◽

Cone Opsins ◽

Retinal Information

AbstractColor vision in mammals is based on the expression of at least two cone opsins that are sensitive to different wavelengths of light. Furthermore, retinal pathways conveying color-opponent signals are required for color discrimination. Most of the primates are trichromats, and “color-coded channels” of their retinas are unveiled to a large extent. In contrast, knowledge of cone-selective pathways in nonprimate dichromats is only slowly emerging, although retinas of dichromats like mice or rats are extensively studied as model systems for retinal information processing. Here, we review recent progress of research on color-coded pathways in nonprimate dichromats to identify differences or similarities between di- and trichromatic mammals. In addition, we applied immunohistochemical methods and confocal microscopy to retinas of different species and present data on their neuronal properties, which are expected to contribute to color vision. Basic neuronal features such as the “blue cone bipolar cell” exist in every species investigated so far. Moreover, there is increasing evidence for chromatic OFF channels in dichromats and retinal ganglion cells that relay color-opponent signals to the brain. In conclusion, di- and trichromats share similar retinal pathways for color transmission and processing.

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Influence of macrophages and lymphocytes on the survival and axon regeneration of injured retinal ganglion cells in rats from different autoimmune backgrounds

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2007.05957.x ◽

2007 ◽

Vol 26 (12) ◽

pp. 3475-3485 ◽

Cited By ~ 11

Author(s):

Jian-Min Luo ◽

Ye Zhi ◽

Qing Chen ◽

Ling-Ping Cen ◽

Cheng-Wu Zhang ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Axon Regeneration ◽

Ganglion Cells ◽

Retinal Ganglion

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Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes

10.1101/711762 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicholas M. Tran ◽

Karthik Shekhar ◽

Irene E. Whitney ◽

Anne Jacobi ◽

Inbal Benhar ◽

...

Keyword(s):

Single Cell ◽

Ganglion Cells ◽

Morphological Changes ◽

Retinal Ganglion ◽

Nerve Crush ◽

Adult Retina ◽

Neuronal Types ◽

The Central Nervous System ◽

Differential Gene

SummaryNeuronal types in the central nervous system differ dramatically in their resilience to injury or insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ~80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC, characterized transcriptomic, physiological, and morphological changes that preceded degeneration, and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury, and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

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Demyelination of the Optic Nerve: An Underlying Factor in Glaucoma?

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.701322 ◽

2021 ◽

Vol 13 ◽

Author(s):

Jingfei Xue ◽

Yingting Zhu ◽

Zhe Liu ◽

Jicheng Lin ◽

Yangjiani Li ◽

...

Keyword(s):

Optic Nerve ◽

Inflammatory Responses ◽

Clinical Symptoms ◽

Ganglion Cells ◽

Neuronal Degeneration ◽

Retinal Ganglion ◽

Progressive Degeneration ◽

Treatment Plans ◽

The Central Nervous System ◽

The Relationship

Neurodegenerative disorders are characterized by typical neuronal degeneration and axonal loss in the central nervous system (CNS). Demyelination occurs when myelin or oligodendrocytes experience damage. Pathological changes in demyelination contribute to neurodegenerative diseases and worsen clinical symptoms during disease progression. Glaucoma is a neurodegenerative disease characterized by progressive degeneration of retinal ganglion cells (RGCs) and the optic nerve. Since it is not yet well understood, we hypothesized that demyelination could play a significant role in glaucoma. Therefore, this study started with the morphological and functional manifestations of demyelination in the CNS. Then, we discussed the main mechanisms of demyelination in terms of oxidative stress, mitochondrial damage, and immuno-inflammatory responses. Finally, we summarized the existing research on the relationship between optic nerve demyelination and glaucoma, aiming to inspire effective treatment plans for glaucoma in the future.

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Combined inhibition of apoptosis and necrosis promotes transient neuroprotection of retinal ganglion cells and partial-axon regeneration after optic nerve damage

10.1101/357566 ◽

2018 ◽

Cited By ~ 2

Author(s):

Maki Kayama ◽

Kumiko Omura ◽

Yusuke Murakami ◽

Edith Reshef ◽

Aristomenis Thanos ◽

...

Keyword(s):

Cell Death ◽

Optic Nerve ◽

Axonal Regeneration ◽

Axon Regeneration ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Interacting Protein ◽

Caspase Inhibition ◽

Apoptosis And Necrosis

SUMMARYRetinal ganglion cell (RGC) death is the hallmark of glaucoma. Axonal injury is thought to precede RGC loss in glaucoma, and thus studies using an optic nerve (ON) crush model have been widely used to investigate mechanisms of cell death that are common to both conditions. Prior work has focused on the involvement of caspases in RGC death, but little is known about the contribution of other forms of cell death such as necrosis. In this study we show that receptor interacting protein (RIP) kinase-mediated necrosis normally plays a role in RGC death and acts in concert with caspase-dependent apoptosis. The expression of RIP3, a key activator of RIP1 kinase, as well as caspase activity, increased following ON injury. Caspase inhibition alone failed to provide substantial protection to injured RGCs and unexpectedly exacerbated necrosis. In contrast, pharmacologic or genetic inhibition of RIP kinases in combination with caspase blockade delayed both apoptotic and necrotic RGC death, although RGCs still continued to die. Furthermore, inhibition of RIP1 kinase promoted a moderate level of axon regeneration that was only minimal affected by caspase inhibition. In conclusion, multiple approaches are required for effective RGC death prevention and axonal regeneration. Further studies are needed to elucidate more effective long term strategies that can lead to sustained neuroprotection and regeneration.

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