scholarly journals TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy

2021 ◽  
pp. dmm.047548
Author(s):  
Rachel Atkinson ◽  
Jacqueline Leung ◽  
James Bender ◽  
Matthew Kirkcaldie ◽  
James Vickers ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cells ◽  
Neuronal Cell ◽  
Detailed Examination ◽  
Transduction Efficiency ◽  
Nuclear Localization Sequence ◽  
New Model ◽  
Cellular Effects ◽  
The Impact

Mislocalization of the TAR DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm is a common feature of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The downstream in vivo cellular effects of this mislocalization are not well understood. To investigate the impact of mislocalized TDP-43 on neuronal cell bodies, axons and axonal terminals, we utilized the mouse visual system to create a new model of TDP-43 proteinopathy. Mouse (C57BL/6J) retinal ganglion cells (RGCs) were transduced with GFP-tagged human wildtype TDP-43 (hTDP-WT-GFP) and human TDP-43 with a mutation in the nuclear localization sequence (hTDP-ΔNLS-GFP), to cause TDP-43 mislocalization, with ∼60% transduction efficiency achieved. Expression of both hTDP-WT-GFP and hTDP-ΔNLS-GFP resulted in changes to neurofilament expression, with cytoplasmic TDP-43 being associated with significantly (p<0.05) increased neurofilament heavy expression in the cell soma, and both forms of altered TDP-43 leading to significantly (p<0.05) decreased numbers of neurofilament-positive axons within the optic nerve. Alterations to neurofilament proteins were associated with significantly (p<0.05) increased microglial density in the optic nerve and retina. Furthermore expression of hTDP-WT-GFP was associated with a significant (p<0.05) increase in pre-synaptic input into RGCs in the retina. The current study has developed a new model allowing detailed examination of alterations to TDP-43 and will contribute to the knowledge of TDP-43-mediated neuronal alterations and degeneration.

scholarly journals Rescue of retinal ganglion cells in optic nerve injury using cell-selective AAV mediated delivery of SIRT1

Gene Therapy ◽  
2021 ◽  
Author(s):  
Ahmara G. Ross ◽  
Devin S. McDougald ◽  
Reas S. Khan ◽  
Thu T. Duong ◽  
Kimberly E. Dine ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cell ◽  
Optic Neuropathy ◽  
Visual Function ◽  
Ganglion Cells ◽  
Transduction Efficiency ◽  
Retinal Ganglion ◽  
Optokinetic Response ◽  
Nerve Crush

AbstractSIRT1 prevents retinal ganglion cell (RGC) loss in models of optic neuropathy following pharmacologic activation or genetic overexpression. The exact mechanism of loss is not known, prior evidence suggests this is through oxidative stress to either neighboring cells or RGC specifically. We investigated the neuroprotective potential of RGC-selective SIRT1 gene therapy in the optic nerve crush (ONC) model. We hypothesized that AAV-mediated overexpression of SIRT1 in RGCs reduces RGC loss, thereby preserving visual function. Cohorts of C57Bl/6J mice received intravitreal injection of experimental or control AAVs using either a ganglion cell promoter or a constitutive promoter and ONC was performed. Visual function was examined by optokinetic response (OKR) for 7 days following ONC. Retina and optic nerves were harvested to investigate RGC survival by immunolabeling. The AAV7m8-SNCG.SIRT1 vector showed 44% transduction efficiency for RGCs compared with 25% (P > 0.05) by AAV2-CAG.SIRT1, and AAV7m8-SNCG.SIRT1 drives expression selectively in RGCs in vivo. Animals modeling ONC demonstrated reduced visual acuity compared to controls. Intravitreal delivery of AAV7m8-SNCG.SIRT1 mediated significant preservation of the OKR and RGC survival compared to AAV7m8-SNCG.eGFP controls, an effect not seen with the AAV2 vector. RGC-selective expression of SIRT1 offers a targeted therapy for an animal model with significant ganglion cell loss. Over-expression of SIRT1 through AAV-mediated gene transduction suggests a RGC selective component of neuro-protection using the ONC model. This study expands our understanding of SIRT1 mediated neuroprotection in the context of compressive or traumatic optic neuropathy, making it a strong therapeutic candidate for testing in all optic neuropathies.

scholarly journals The Potential of Visible and Far-Red to Near-Infrared Light in Glaucoma Neuroprotection

2021 ◽  
Vol 11 (13) ◽  
pp. 5872
Author(s):  
Loredana Bergandi ◽  
Francesca Silvagno ◽  
Giulia Grisolia ◽  
Antonio Ponzetto ◽  
Emilio Rapetti ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Ganglion Cells ◽  
Nerve Repair ◽  
Treatment Strategies ◽  
Neuronal Cell ◽  
Infrared Light ◽  
Near Infrared Light ◽  
The Impact

Alternative treatment strategies are necessary to reduce the severity of glaucoma, a group of eye conditions that progressively damage the optic nerve and impair vision. The aim of this review is to gain insight into potentially exploitable molecular mechanisms to slow down the death of retinal ganglion cells (RGCs), a fundamental element in the pathophysiology of all forms of glaucoma, and to stimulate adult optic nerve repair. For this purpose, we focus our analysis on both visible and far-red to near-infrared light photobiomodulation (PBM) as phototherapeutic agents, which were recently proposed in RGCs, and on the nerve lamina region neural progenitor cell (ONLR-NPC) niche. Both are suggested as potential strategies in glaucoma neuroprotection. We discuss the impact of beneficial molecular effects of PBM on both mitochondrial derangement and the alteration of ion fluxes that are considered important causes of RGC damage, as well as on the stimulation of progenitor cells. We suggest these are the most promising approaches to prevent excessive neuronal cell loss. We describe the experimental evidence supporting the validity of PBM therapy which, despite being a safe, non-invasive, inexpensive, and easy to administer procedure, has not yet been fully explored in the clinical practice of glaucoma treatment.

scholarly journals Isolation and structural elucidation of dimeric epigallocatechin-3-gallate autoxidation products and their antioxidant capacity

2021 ◽  
Author(s):  
Julian Alfke ◽  
Uta Kampermann ◽  
Svetlana Kalinina ◽  
Melanie Esselen
Keyword(s):  
Antioxidant Capacity ◽  
Antioxidant Properties ◽  
Cd Spectroscopy ◽  
Trolox Equivalent Antioxidant Capacity ◽  
Published Data ◽  
Dietary Polyphenols ◽  
Cellular Effects ◽  
The Impact

AbstractDietary polyphenols like epigallocatechin-3-gallate (EGCG)—which represents the most abundant flavan-3-ol in green tea—are subject of several studies regarding their bioactivity and health-related properties. On many occasions, cell culture or in vitro experiments form the basis of published data. Although the stability of these compounds is observed to be low, many reported effects are directly related to the parent compounds whereas the impact of EGCG degradation and autoxidation products is not yet understood and merely studied. EGCG autoxidation products like its dimers theasinensin A and D, “P2” and oolongtheanin are yet to be characterized in the same extent as their parental polyphenol. However, to investigate the bioactivity of autoxidation products—which would minimize the discrepancy between in vitro and in vivo data—isolation and structure elucidation techniques are urgently needed. In this study, a new protocol to acquire the dimers theasinensin A and D as well as oolongtheanin is depicted, including a variety of spectroscopic and quadrupole time-of-flight high-resolution mass spectrometric (qTOF-HRMS) data to characterize and assign these isolates. Through nuclear magnetic resonance (NMR) spectroscopy, polarimetry, and especially circular dichroism (CD) spectroscopy after enzymatic hydrolysis the complementary atropisomeric stereochemistry of the isolated theasinensins is illuminated and elucidated. Lastly, a direct comparison between the isolated EGCG autoxidation products and the monomer itself is carried out regarding their antioxidant properties featuring Trolox equivalent antioxidant capacity (TEAC) values. These findings help to characterize these products regarding their cellular effects and—which is of special interest in the flavonoid group—their redox properties.

scholarly journals Optical coherence tomography: how it all began, and present-time diagnostic capabilities

2014 ◽  
Vol 7 (2) ◽  
pp. 60-68 ◽  
Author(s):  
Yuriy Sergeyevich Astakhov ◽  
Svetlana Georgiyevna Belekhova
Keyword(s):  
Optical Coherence Tomography ◽  
Optic Nerve ◽  
Practical Interest ◽  
Detailed Examination ◽  
Modern Method ◽  
Optical Coherence ◽  
Continual Improvement ◽  
Diagnostic Capabilities ◽  
Very High

The optical coherence tomography is a modern method to assist the ophthalmologist examine the eye fundus. Tomographs have a very high resolution and give the ophthalmologist a in real-time mode in vivo a detailed examination of retinal, optic nerve and choroidal structures. A continual improvement of this technique offers great opportunities and is not only of scientific but also of practical interest.

scholarly journals Novel Use of PLGA Microspheres to Create an Animal Model of Glaucoma with Progressive Neuroretinal Degeneration

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 237
Author(s):  
David Garcia-Herranz ◽  
Maria Jesus Rodrigo ◽  
Manuel Subias ◽  
Teresa Martinez-Rincon ◽  
Silvia Mendez-Martinez ◽  
...  
Keyword(s):  
Animal Model ◽  
Optic Nerve ◽  
Ganglion Cells ◽  
Histological Study ◽  
Clinical Signs ◽  
Plga Microspheres ◽  
Chronic Glaucoma ◽  
Progressive Degeneration ◽  
Study Results

Progressive degeneration of neuroretinal tissue with maintained elevated intraocular pressure (IOP) to simulate chronic glaucoma was produced by intracameral injections of poly (lactic-co-glycolic) acid (PLGA) microspheres (Ms) in rat eyes. The right eye of 39 rats received different sizes of PLGA-Ms (2 µL suspension; 10% w/v): 14 with 38–20 µm Ms (Ms38/20 model) and 25 with 20–10 µm particles (Ms20/10 model). This novel glaucoma animal model was compared to the episcleral vein sclerosis (EPI) model (25 eyes). Injections were performed at baseline, two, four and six weeks. Clinical signs, IOP, retina and optic nerve thicknesses (using in vivo optical coherence tomography; OCT), and histological studies were performed. An IOP increment was observed in all three groups, however, the values obtained from the PLGA-Ms injection resulted lower with a better preservation of the ocular surface. In fact, the injection of Ms20/10 created a gentler, more progressive, and more sustained increase in IOP. This IOP alteration was correlated with a significant decrease in most OCT parameters and in histological ganglion-cell count for the three conditions throughout the eight-week follow-up. In all cases, progressive degeneration of the retina, retinal ganglion cells and optic nerve, simulating chronic glaucoma, was detected by OCT and corroborated by histological study. Results showed an alternative glaucoma model to the well-known episcleral vein model, which was simpler to perform, more reproducible and easier to monitor in vivo.

scholarly journals Longitudinal In Vivo Imaging of Retinal Ganglion Cells and Retinal Thickness Changes Following Optic Nerve Injury in Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e40352 ◽  
Author(s):  
Balwantray C. Chauhan ◽  
Kelly T. Stevens ◽  
Julie M. Levesque ◽  
Andrea C. Nuschke ◽  
Glen P. Sharpe ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Nerve Injury ◽  
Retinal Ganglion Cells ◽  
In Vivo Imaging ◽  
Ganglion Cells ◽  
Retinal Thickness ◽  
Retinal Ganglion ◽  
Optic Nerve Injury

scholarly journals The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1593
Author(s):  
Nicole A. Muench ◽  
Sonia Patel ◽  
Margaret E. Maes ◽  
Ryan J. Donahue ◽  
Akihiro Ikeda ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Pressure Gradient ◽  
Ganglion Cells ◽  
Mitochondrial Dynamics ◽  
Metabolic Stress ◽  
Neuronal Cell ◽  
Retinal Ganglion ◽  
Support Functions ◽  
Dynamics And Function ◽  
And Function

The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs.

scholarly journals Mesoscopic cortical network reorganization during recovery of partial optic nerve injury in GCaMP6s mice

2020 ◽  
Author(s):  
Marianne Groleau ◽  
Mojtaba Nazari-Ahangarkolaee ◽  
Matthieu P. Vanni ◽  
Jacqueline L. Higgins ◽  
Anne-Sophie Vézina Bédard ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Optic Nerve ◽  
Nerve Injury ◽  
Cortical Plasticity ◽  
Ganglion Cells ◽  
Wide Field ◽  
Optic Nerve Injury ◽  
Nerve Crush ◽  
Correlated Activity

AbstractAs the residual vision following a traumatic optic nerve injury can spontaneously recover over time, we explored the plasticity of cortical networks during the early post-optic nerve crush (ONC) phase. Using in vivo wide-field calcium imaging on awake Thy1-GCaMP6s mice, we characterized resting state and evoked cortical activity before, during, and 30 days after ONC. The recovery of monocular visual acuity and depth perception was evaluated at the same time points. Cortical responses to an LED flash decreased in the contralateral hemisphere in the primary visual cortex and in the secondary visual areas following the ONC, but was partially rescued between 3 and 5 days post-ONC, remaining stable thereafter. The connectivity between visual and non-visual regions was disorganized after the crush, as shown by a decorrelation, but correlated activity was restored 30 days after the injury. The number of surviving retinal ganglion cells dramatically dropped and remained low. At the behavioral level, the ONC resulted in visual acuity loss on the injured side and an increase in visual acuity with the non-injured eye. In conclusion, our results show a reorganization of connectivity between visual and associative cortical areas after an ONC, which is indicative of spontaneous cortical plasticity.

scholarly journals Citrus Naringenin Increases Neuron Survival in Optic Nerve Crush Injury Model by Inhibiting JNK-JUN Pathway

2021 ◽  
Vol 23 (1) ◽  
pp. 385
Author(s):  
Jie Chen ◽  
Hui Li ◽  
Changming Yang ◽  
Yinjia He ◽  
Tatsuo Arai ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Nerve Injury ◽  
Ganglion Cells ◽  
Crush Injury ◽  
Optic Nerve Crush ◽  
Nerve Crush ◽  
Injury Model ◽  
Nerve Crush Injury

Traumatic nerve injury activates cell stress pathways, resulting in neuronal death and loss of vital neural functions. To date, there are no available neuroprotectants for the treatment of traumatic neural injuries. Here, we studied three important flavanones of citrus components, in vitro and in vivo, to reveal their roles in inhibiting the JNK (c-Jun N-terminal kinase)-JUN pathway and their neuroprotective effects in the optic nerve crush injury model, a kind of traumatic nerve injury in the central nervous system. Results showed that both neural injury in vivo and cell stress in vitro activated the JNK-JUN pathway and increased JUN phosphorylation. We also demonstrated that naringenin treatment completely inhibited stress-induced JUN phosphorylation in cultured cells, whereas nobiletin and hesperidin only partially inhibited JUN phosphorylation. Neuroprotection studies in optic nerve crush injury mouse models revealed that naringenin treatment increased the survival of retinal ganglion cells after traumatic optic nerve injury, while the other two components had no neuroprotective effect. The neuroprotection effect of naringenin was due to the inhibition of JUN phosphorylation in crush-injured retinal ganglion cells. Therefore, the citrus component naringenin provides neuroprotection through the inhibition of the JNK-JUN pathway by inhibiting JUN phosphorylation, indicating the potential application of citrus chemical components in the clinical therapy of traumatic optic nerve injuries.

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