Inherited glaucoma in DBA/2J mice: Pertinent disease features for studying the neurodegeneration

2005 ◽  
Vol 22 (5) ◽  
pp. 637-648 ◽  
Author(s):  
RICHARD T. LIBBY ◽  
MICHAEL G. ANDERSON ◽  
IOK-HOU PANG ◽  
ZACHARY H. ROBINSON ◽  
OLGA V. SAVINOVA ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cells ◽  
The Elderly ◽  
Nerve Degeneration ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Future Studies ◽  
Age Related ◽  
Iop Elevation ◽  
Mechanistic Basis

The glaucomas are neurodegenerative diseases involving death of retinal ganglion cells and optic nerve head excavation. A major risk factor for this neurodegeneration is a harmfully elevated intraocular pressure (IOP). Human glaucomas are typically complex, progressive diseases that are prevalent in the elderly. Family history and genetic factors are clearly important in human glaucoma. Mouse studies have proven helpful for investigating the genetic and mechanistic basis of complex diseases. We previously reported inherited, age-related progressive glaucoma in DBA/2J mice. Here, we report our updated findings from studying the disease in a large number of DBA/2J mice. The period when mice have elevated IOP extends from 6 months to 16 months, with 8–9 months representing an important transition to high IOP for many mice. Optic nerve degeneration follows IOP elevation, with the majority of optic nerves being severely damaged by 12 months of age. This information should help with the design of experiments, and we present the data in a manner that will be useful for future studies of retinal ganglion cell degeneration and optic neuropathy.

scholarly journals Oral pyruvate prevents glaucomatous neurodegeneration

2020 ◽  
Author(s):  
Pete A Williams ◽  
Jeffrey M Harder ◽  
Chelsea Guymer ◽  
John P M Wood ◽  
Evangelia Daskalaki ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Ganglion Cells ◽  
Nerve Degeneration ◽  
Columbia University ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Oral Supplementation ◽  
Pressure Sensitive ◽  
Age Related ◽  
Clinical Models

AbstractIntraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Converging evidence indicates that age-related bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure. To investigate further, we used metabolomics and RNA-sequencing to examine early glaucoma in DBA/2J mice. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Oral supplementation of pyruvate strongly protected from neurodegeneration in pre-clinical models of glaucoma. We detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration. Bioenergetic enhancement, in combination with intraocular pressure reduction, therefore provides a readily translatable strategy that warrants investigation in clinical trials.FundingVetenskapsrådet 2018-02124 and StratNeuro StartUp grant (PAW). Pete Williams is supported by the Karolinska Institutet in the form of a Board of Research Faculty Funded Career Position and by St. Erik Eye Hospital philanthropic donations. EY011721 and the Barbra and Joseph Cohen Foundation and startup funds from Columbia University (SWMJ). Simon John is an Investigator of HHMI.

Pathways of regenerated retinotectal axons in goldfish

Development ◽  
1986 ◽  
Vol 93 (1) ◽  
pp. 1-28
Author(s):  
Claudia A. O. Stuermer
Keyword(s):  
Optic Nerve ◽  
Retinal Ganglion Cells ◽  
Normal Development ◽  
Ganglion Cells ◽  
Optic Tract ◽  
Spatiotemporal Pattern ◽  
Retinal Ganglion ◽  
Retinal Axons ◽  
Age Related ◽  
Regenerated Fibres

This study investigates the order of regenerating retinal axons in the goldfish. The spatiotemporal pattern of axon regrowth was assessed by applying horseradish peroxidase (HRP) to regenerating axons in the optic tract at various times after optic nerve section and by analysing the distribution of retrogradely labelled ganglion cells in retina. At all regeneration stages labelled ganglion cells were widely distributed over the retina. There was no hint that axons from central (older) ganglion cells might regrow earlier, and peripheral (younger) ganglion cells later, as occurs in normal development. The absence of an age-related ordering in the regenerated optic nerve was demonstrated by labelling a few axon bundles intraorbitally with HRP (Easter, Rusoff & Kish, 1981) caudal to the previous cut. The retrogradely labelled cells in retina were randomly distributed in regenerates andnot clustered in annuli as in normals. Tracing regenerating axons which were stained anterogradelyfrom intraretinal HRP applications or retrogradely from single labelled tectal fascicles illustrated the fact that the regenerating axons coursed in abnormal routes in the optic nerve and tract. On the surface of the tectum regenerated fibres re-established a fascicle fan. The retinal origin of tectal fascicles was assessed by labelling individual peripheral, intermediate and rostral fascicles with HRP. The retrogradely labelled ganglion cells in the retina were often more widely distributed than in normals, but were mostly found in peripheral, intermediate and central retina, respectively. The order of fibre departure from each tectal fascicle was revealed by placing HRP either on the fascicle's proximal or on its distal half. With proximal labelling sites labelled ganglion cells were found in the temporal and nasal retina, and with distal labelling sites labelled ganglion cells were confined to nasal retina only. Further, the axonal trajectories of anterogradely labelled dorsotemporal retinal ganglion cells were compared to those of dorsonasal retinal ganglion cells in tectal whole mounts. Dorsotemporal axons were confined to the rostral tectal half, whereas dorsonasal axons followed fascicular routes into the fascicles' distal end and reached into caudal tectum. This suggests that the fibres exited along their fascicle's course in a temporonasal sequence. Thus in the tectum, fibres in fascicles restore a gross spatial and age-related order and tend to follow their normal temporonasal sequence of exit.

scholarly journals Role of Heat Shock Proteins in Glaucoma

2019 ◽  
Vol 20 (20) ◽  
pp. 5160 ◽  
Author(s):  
Teresa Tsai ◽  
Pia Grotegut ◽  
Sabrina Reinehr ◽  
Stephanie C. Joachim
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Retinal Ganglion Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ganglion Cells ◽  
Nerve Degeneration ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Shock Proteins

Glaucoma, one of the most common causes of blindness worldwide, is a multifactorial neurodegenerative disease characterized by damage of retinal ganglion cells and optic nerve degeneration. However, the exact mechanism leading to glaucoma is still not understood. Evidences suggest an immunological involvement in the pathogenesis. Among other immune responses, altered autoantibody patterns were found in glaucoma patients. Especially elevated antibody levels against heat shock proteins (HSPs), like HSP27 or HSP60, were identified. In an animal model, an immunization with these HSPs induced a pressure-independent retinal ganglion cell degeneration and axon loss, hence mimicking glaucoma-like damage. In addition, development of autoreactive antibodies, as well as a glia and T-cell activation, were described in these animals. Recently, we noted that intravitreal HSP27 injection likewise led to a degeneration of retinal ganglion cells and their axons. Therefore, HSP27 might have a direct damaging effect on retinal cells, and might play a key role in glaucoma.

scholarly journals Proteomic Analysis of Retinal Tissue in an S100B Autoimmune Glaucoma Model

Biology ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 16
Author(s):  
Sabrina Reinehr ◽  
Annika Guntermann ◽  
Janine Theile ◽  
Lara Benning ◽  
Pia Grotegut ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Optic Nerve ◽  
Ganglion Cells ◽  
Cell Activity ◽  
Study Groups ◽  
Mass Spectrometry Analysis ◽  
Nerve Degeneration ◽  
Heat Shock Protein 60 ◽  
Retinal Ganglion ◽  
Spectrometry Analysis

Glaucoma is a neurodegenerative disease that leads to damage of retinal ganglion cells and the optic nerve. Patients display altered antibody profiles and increased antibody titer, e.g., against S100B. To identify the meaning of these antibodies, animals were immunized with S100B. Retinal ganglion cell loss, optic nerve degeneration, and increased glial cell activity were noted. Here, we aimed to gain more insights into the pathophysiology from a proteomic point of view. Hence, rats were immunized with S100B, while controls received sodium chloride. After 7 and 14 days, retinae were analyzed through mass spectrometry and immunohistology. Using data-independent acquisition-based mass spectrometry, we identified more than 1700 proteins on a high confidence level for both study groups, respectively. Of these 1700, 43 proteins were significantly altered in retinae after 7 days and 67 proteins revealed significant alterations at 14 days. For example, α2-macroglobulin was found significantly increased not only by mass spectrometry analysis, but also with immunohistological staining in S100B retinae at 7 and 14 days. All in all, the identified proteins are often associated with the immune system, such as heat shock protein 60. Once more, these data underline the important role of immunological factors in glaucoma pathogenesis.

scholarly journals Dual SMAD inhibition and Wnt inhibition enable efficient and reproducible differentiations of induced pluripotent stem cells into retinal ganglion cells

2019 ◽  
Author(s):  
Venkata R. M. Chavali ◽  
Naqi Haider ◽  
Sonika Rathi ◽  
Vrathasha Vrathasha ◽  
Teja Alapati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Optic Nerve ◽  
Visual Field ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Visual Field Loss ◽  
Nerve Degeneration ◽  
Retinal Ganglion

AbstractGlaucoma is a group of progressive optic neuropathies that share common biological and clinical characteristics including irreversible changes to the optic nerve and visual field loss caused by death of retinal ganglion cells (RGCs). The loss of RGCs manifests as characteristic cupping or optic nerve degeneration, resulting in visual field loss in patients with Glaucoma. Published studies on in vitro RGC differentiation from stem cells utilized classical RGC signaling pathways mimicking retinal development in vivo. Although many strategies allowed for the generation of RGCs, increased variability between experiments and lower yield hampered the cross comparison between individual lines and between experiments. To address this critical need, we developed a reproducible chemically defined in vitro methodology for generating retinal progenitor cell (RPC) populations from iPSCs, that are efficiently directed towards RGC lineage. Using this method, we reproducibly differentiated iPSCs into RGCs with greater than 80% purity, without any genetic modifications. We used small molecules and peptide modulators to inhibit BMP, TGF-β (SMAD), and canonical Wnt pathways that reduced variability between iPSC lines and yielded functional and mature iPSC-RGCs. Using CD90.2 antibody and Magnetic Activated Cell Sorter (MACS) technique, we successfully purified Thy-1 positive RGCs with nearly 95% purity.

scholarly journals Cochlin and glaucoma: A mini-review

2005 ◽  
Vol 22 (5) ◽  
pp. 605-613 ◽  
Author(s):  
SANJOY K. BHATTACHARYA ◽  
NEAL S. PEACHEY ◽  
JOHN W. CRABB
Keyword(s):  
Optic Nerve ◽  
Collagen Type ◽  
Late Onset ◽  
Open Angle Glaucoma ◽  
Nerve Damage ◽  
Contributory Factor ◽  
Retinal Ganglion ◽  
Cell Degeneration ◽  
Future Studies ◽  
Optic Nerve Damage

Primary open angle glaucoma (POAG) is a leading cause of late onset, progressive, irreversible blindness and, although its etiology is poorly understood, elevated intraocular pressure (IOP) often appears to be a contributory factor. Proteomic and Western analyses of trabecular meshwork (TM) from patients with POAG and age-matched controls originally implicated cochlin as possibly contributing to glaucoma pathogenesis. Cochlin deposits were subsequently detected in glaucomatous but not in control TM and older glaucomatous TM was found to contain higher levels of cochlin and significantly lower amounts of collagen type II. More recently, similar results were reported in DBA/2J mice, which at older ages develop elevated IOP, retinal ganglion cell degeneration, and optic nerve damage. Notably, cochlin was absent in TM from C57BL/6J, CD1, and BALBc/ByJ mice, which do not exhibit elevated IOP or glaucoma. Cochlin was found in the TM of very young DBA/2J mice, prior to elevated IOP, suggesting that over time the protein may contribute to the events leading to increased IOP and optic nerve damage. Here we review these findings and describe how future studies in DBA/2J mice can help resolve whether cochlin plays a causal role in mechanisms of POAG and elevated IOP.

scholarly journals Loss of Binocular Responses and Reduced Retinal Convergence During the Period of Retinogeniculate Axon Segregation

2006 ◽  
Vol 96 (5) ◽  
pp. 2775-2784 ◽  
Author(s):  
Jokūbas Z̆iburkus ◽  
William Guido
Keyword(s):  
Optic Nerve ◽  
Ganglion Cells ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Retinal Ganglion ◽  
Retinal Projections ◽  
Axon Terminals ◽  
Age Related ◽  
Dorsal Lateral Geniculate ◽  
Anterograde Labeling

In the developing mammalian visual system, axon terminals from the two eyes overlap in the dorsal lateral geniculate nucleus (LGN) but then undergo a period of refinement and segregate to form distinct eye-specific domains. We report on the changes in synaptic transmission that occur in rodent LGN during the period of retinogeniculate axon segregation by using anterograde labeling techniques in conjunction with an in vitro preparation where large segments of each optic nerve are preserved. Anterograde labeling of retinal projections in early postnatal day (P) rats with cholera toxin β subunit indicated an age-related recession in uncrossed retinal projections. Between P2 and P5 uncrossed projections occupied as much as 50% of the LGN and overlapped substantially with crossed projections. Between the first and second postnatal week uncrossed projections receded, so by P14 they assumed an adultlike profile occupying 15–20% of LGN and showed little or no overlap with crossed projections. The postsynaptic responses of LGN cells evoked by the separate stimulation of each optic nerve indicated that before P14, many relay cells were binocularly innervated and received at least four to six inputs from each eye. However, these features of retinogeniculate connectivity were transient and their attrition occurred in concert with a retraction of retinal arbors into nonoverlapping, eye-specific regions. By P18 cells were monocularly innervated and received input from one to three retinal ganglion cells. These results provide a better understanding of the underlying changes in synaptic circuitry that occur during the anatomical segregation of retinal inputs into eye-specific territories.

scholarly journals Transfer of the Experimental Autoimmune Glaucoma Model from Rats to Mice—New Options to Study Glaucoma Disease

2019 ◽  
Vol 20 (10) ◽  
pp. 2563 ◽  
Author(s):  
Sabrina Reinehr ◽  
Jacqueline Reinhard ◽  
Susanne Wiemann ◽  
Karoline Hesse ◽  
Christina Voss ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Ganglion Cells ◽  
Nerve Degeneration ◽  
Retinal Ganglion ◽  
Retinal Neurons ◽  
Optic Nerves ◽  
Gabaergic Synapses ◽  
Optic Nerve Degeneration ◽  
Experimental Autoimmune

Studies have suggested an involvement of the immune system in glaucoma. Hence, a rat experimental autoimmune glaucoma model (EAG) was developed to investigate the role of the immune response. Here, we transferred this model into mice. Either 0.8 mg/mL of the optic nerve antigen homogenate (ONA; ONA 0.8) or 1.0 mg/mL ONA (ONA 1.0) were injected in 129/Sv mice. Controls received sodium chloride. Before and 6 weeks after immunization, the intraocular pressure (IOP) was measured. At 6 weeks, retinal neurons, glia cells, and synapses were analyzed via immunohistology and quantitative real-time PCR (RT-qPCR). Additionally, optic nerves were examined. The IOP stayed in the normal physiological range throughout the study (p > 0.05). A significant reduction of retinal ganglion cells (RGCs) was noted in both immunized groups (p < 0.001). Remodeling of glutamatergic and GABAergic synapses was seen in ONA 1.0 retinas. Furthermore, both ONA groups revealed optic nerve degeneration and macrogliosis (all: p < 0.001). An increase of activated microglia was noted in ONA retinas and optic nerves (p < 0.05). Both ONA concentrations led to RGC loss and optic nerve degeneration. Therefore, the EAG model was successfully transferred from rats to mice. In further studies, transgenic knockout mice can be used to investigate the pathomechanisms of glaucoma more precisely.

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.

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