The BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models neurodegeneration, including glaucomatous optic neuropathy (glaucoma), which degrades the retinal ganglion cell (RGC) axonal projection visual brain. Glaucoma is commonly associated with increased sensitivity intraocular pressure (IOP) and involves a proximal program that leads RGC dendritic pruning distal underlies axonopathy projection. While genetic deletion Bcl2-associated X protein...

Identification of early adaptive and maladaptive neuronal stress responses is an important step in developing targeted neuroprotective therapies for degenerative disease. In glaucoma, retinal ganglion cells (RGCs) their axons undergo progressive degeneration resulting from driven by sensitivity to intraocular pressure (IOP). Despite that can effectively manage IOP many patients progress vision loss, necessitating development neuronal-based therapies. Evidence experimental models glaucoma...

Early challenges to axonal physiology, active transport, and ultrastructure are endemic age-related neurodegenerative disorders, including those affecting the optic nerve. Chief among these, glaucoma causes irreversible vision loss through sensitivity intraocular pressure (IOP) that retinal ganglion cell (RGC) axons, which comprise RGC axonopathy includes distal proximal progression implicates a slow form of Wallerian degeneration. In multiple disease models, inducible glaucoma, expression...

Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in nerve degeneration and loss retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation intraocular pressure (IOP) the most attributable risk factor for developing lowering IOP currently only available therapy. However, despite IOP, neurodegenerative effects persist some patients. Hence, it would be beneficial develop approaches promote neuroprotection RGCs addition...

Lenadogene nolparvovec (GS010) was developed to treat a point mutation in mitochondrial ND4 that causes Leber hereditary optic neuropathy. GS010 delivers human cDNA encoding wild-type packaged into an rAAV2/2 vector transduces retinal ganglion cells, induce allotopic expression of hybrid ND4. clinical trials improved best-corrected visual acuity (BCVA) up 5 years after treatment. Interestingly, unilateral treatment BCVA bilaterally. Subsequent studies revealed DNA tissues contralateral the...

Purpose: The α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors (AMPAR) subunits can be posttranscriptionally modified by alternative splicing forming flip and flop isoforms. We determined if an ischemia-like insult to retinal ganglion cells (RGCs) increases AMPAR susceptibility s-AMPA–mediated excitotoxicity through changes in posttranscriptional Methods: Purified neonatal rat RGCs were subjected either glucose deprivation (GD) or oxygen/glucose (OGD) conditions followed...

Glaucoma is an age-related neurodegenerative disease that commonly associated with sensitivity to intraocular pressure. The selectively targets retinal ganglion cells (RGCs) and constituent axons. RGC axons are rich in voltage-gated sodium channels, which essential for action potential initiation regeneration. Here, we identified voltage-dependent channel, NaV1.2, the retina, examined how this channel contributes light responses, monitored NaV1.2 mRNA protein expression retina during...

The transient receptor potential vanilloid one (TRPV1) in the central nervous system may contribute to homeostatic plasticity by regulating intracellular Ca2+, which becomes unbalanced age-related neurodegenerative diseases, including Alzheimer's and Huntington's. Glaucomatous optic neuropathy – world's leading cause of irreversible blindness involves progressive degeneration retinal ganglion cell (RGC) axons nerve through sensitivity stress related intraocular pressure (IOP). In models...

Early progression in neurodegenerative disease involves challenges to homeostatic processes, including those controlling axonal excitability and dendritic organization. In glaucoma, the leading cause of irreversible blindness, stress from intraocular pressure (IOP) causes degeneration retinal ganglion cells (RGC) their axons which comprise optic nerve. Previously, we discovered that early induces axogenic, voltage-gated enhanced RGCs, even as complexity retina reduces. Here, investigate a...

Optic neuropathies are a major cause of visual disabilities worldwide, causing irreversible vision loss through the degeneration retinal ganglion cell (RGC) axons, which comprise optic nerve. Chief among these is glaucoma, in sensitivity to intraocular pressure (IOP) leads RGC axon dysfunction followed by outright projection. Current treatments focus entirely on lowering IOP topical hypotensive drugs, surgery facilitate aqueous fluid outflow, or both. Despite this investment time and...

Vision loss through the degeneration of retinal ganglion cell (RGC) axons occurs in both chronic and acute conditions that target optic nerve. These include glaucoma, which sensitivity to intraocular pressure (IOP) causes early RGC axonal dysfunction, nerve trauma, rapid axon from site injury. In each case, is irreversible, necessitating new therapeutics protect, repair, regenerate axons. Recently, we demonstrated reparative capacity using collagen mimetic peptides (CMPs) heal fragmented...

Abstract Background Cell-to-cell communication is vital for tissues to respond, adapt, and thrive in the prevailing milieu. Several mechanisms mediate intercellular signaling, including tunneling nanotubes, gap junctions, extracellular vesicles (EV). Depending on local systemic conditions, EVs may contain cargoes that promote survival, neuroprotection, or pathology. Our understanding of pathologic signaling has been bolstered by disease models using neurons derived from human pluripotent...

Purpose: Axons depend on long-range transport of proteins and organelles which increases susceptibility to metabolic stress in disease. The axon initial segment (AIS) is particularly vulnerable due the high bioenergetic demand action potential generation. Here, we prepared retinal ganglion cells derived from human embryonic stem (hRGCs) probe how axonal alters AIS morphology. Methods: hRGCs were cultured coverslips or microfluidic platforms. We assayed specification morphology by...

Neuronal type-specific physiologic heterogeneity can be driven by both extrinsic and intrinsic mechanisms. In retinal ganglion cells (RGCs), which carry visual information from the retina to central targets, evidence suggests properties shaping action potential (AP) generation significantly impact responses of RGCs stimuli. Here, we explored how differences in excitability further distinguish two RCG types with distinct presynaptic circuits, alpha ON-sustained (αON-S) OFF-sustained (αOFF-S)...

Optic neuropathies are characterized by degeneration of retinal ganglion cell axonal projections to the brain, including acute conditions like optic nerve trauma and progressive such as glaucoma. Despite different aetiologies, axon in traumatic neuropathy glaucoma share common pathological signatures. We compared how early pathogenesis influence function mouse projection. assessed pathology measuring anterograde transport from retina superior colliculus, current-evoked compound action...

Cell replacement therapies may be key in achieving functional recovery neurodegenerative optic neuropathies diseases such as glaucoma. One strategy that holds promise this regard is the use of human embryonic stem cell and induced pluripotent stem-derived retinal ganglion cells (hRGCs). Previous hRGC transplantation studies have shown modest success. This part due to low survival integration transplanted host retina. The field further challenged by mixed assays outcome measurements probe...

Purpose: Human retinal ganglion cells (hRGC) derived from human pluripotent stem are promising candidates to model, protect, and replace degenerating RGCs. Here, we examined intrinsic morphologic physiologic development of hRGCs. Methods: We used CRISPR-Cas9 selectively express tdTomato under the RGC-specific promoter, BRN3B. were chemically differentiated into hRGCs cultured up 7 weeks. measured soma area, neurite complexity, synaptic protein, axon-related messenger RNA voltage-dependent...

Glaucoma is a neurodegenerative disease associated with elevated intraocular pressure and characterized by optic nerve axonal degeneration, cupping of the disc, loss retinal ganglion cells (RGCs). The endothelin (ET) system vasoactive peptides (ET-1, ET-2, ET-3) their G-protein coupled receptors (ETA ETB receptors) have been shown to contribute pathophysiology glaucoma. purpose this study was determine whether administration receptor antagonist macitentan neuroprotective RGCs axons when...