Aberrant synaptic input to retinal ganglion cells varies with morphology in a mouse model of retinal degeneration

Here, we use a mouse model (DBA/2J) to readdress the location of insult(s) to retinal ganglion cells (RGCs) in glaucoma. We localize an early sign of axon damage to an astrocyte-rich region of the optic nerve just posterior to the retina, analogous to the lamina cribrosa. In this region, a network of astrocytes associates intimately with RGC axons. Using BAX-deficient DBA/2J mice, which retain all of their RGCs, we provide experimental evidence for an insult within or very close to the lamina in the optic nerve. We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina. In contrast, axon segments in the lamina and behind the eye degenerate. Finally, the Wlds allele, which is known to protect against insults to axons, strongly protects against DBA/2J glaucoma and preserves RGC activity as measured by pattern electroretinography. These experiments provide strong evidence for a local insult to axons in the optic nerve.

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Optical Detection of Early Damage in Retinal Ganglion Cells in a Mouse Model of Partial Optic Nerve Crush Injury

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.16-19955 ◽

2016 ◽

Vol 57 (13) ◽

pp. 5665 ◽

Cited By ~ 12

Author(s):

Ji Yi ◽

Zhen Puyang ◽

Liang Feng ◽

Lian Duan ◽

Peiji Liang ◽

...

Keyword(s):

Optic Nerve ◽

Mouse Model ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Crush Injury ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush ◽

Early Damage ◽

Nerve Crush Injury

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Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma

Scientific Reports ◽

10.1038/s41598-021-01077-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Michal Geva ◽

Noga Gershoni-Emek ◽

Luana Naia ◽

Philip Ly ◽

Sandra Mota ◽

...

Keyword(s):

Ganglion Cell ◽

Retinal Degeneration ◽

Retinal Ganglion Cells ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Neuroprotective Effect ◽

Retinal Ganglion ◽

Cell Degeneration ◽

Sigma 1 Receptor ◽

Sigma 1

AbstractOptic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

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Overexpression of BMP4 protects retinal ganglion cells in a mouse model of experimental glaucoma

Experimental Eye Research ◽

10.1016/j.exer.2021.108728 ◽

2021 ◽

pp. 108728

Author(s):

Dongmei Liu ◽

Qinqin Deng ◽

Xinlan Lei ◽

Wei Lu ◽

Qingqing Zhao ◽

...

Keyword(s):

Mouse Model ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Experimental Glaucoma

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Stem cell transplantation rescued a primary open-angle glaucoma mouse model

eLife ◽

10.7554/elife.63677 ◽

2021 ◽

Vol 10 ◽

Author(s):

Siqi Xiong ◽

Ajay Kumar ◽

Shenghe Tian ◽

Eman E Taher ◽

Enzhi Yang ◽

...

Keyword(s):

Stem Cells ◽

Mouse Model ◽

Retinal Ganglion Cells ◽

Primary Open Angle Glaucoma ◽

Therapeutic Potential ◽

Ganglion Cells ◽

Open Angle Glaucoma ◽

Retinal Ganglion ◽

Upregulated Genes

Glaucoma is a leading cause of irreversible blindness. In this study, we investigated if transplanted stem cells are able to rescue a glaucoma mouse model with transgenic myocilin Y437H mutation and explored the possible mechanisms. Human trabecular meshwork stem cells (TMSCs) were intracamerally transplanted which reduced mouse intraocular pressure, increased outflow facility, protected the retinal ganglion cells and preserved their function. TMSC transplantation also significantly increased the TM cellularity, promoted myocilin secretion from TM cells into the aqueous humor to reduce endoplasmic reticulum stress, repaired the TM tissue with extracellular matrix modulation and ultrastructural restoration. Co-culturing TMSCs with myocilin mutant TM cells in vitro promoted TMSCs differentiating into phagocytic functional TM cells. RNA sequencing revealed that TMSCs had upregulated genes related to TM regeneration and neuroprotection. Our results uncovered therapeutic potential of TMSCs for curing glaucoma and elucidated possible mechanisms by which TMSCs achieve the treatment effect.

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