Kv1.1 and Kv1.3 channels contribute to the degeneration of retinal ganglion cells after optic nerve transection in vivo

Koeberle, Paulo D.; Wang, Y; Schlichter, Lyanne C.

doi:10.1038/cdd.2009.113

Cited by 58 publications

(65 citation statements)

References 36 publications

(93 reference statements)

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“…A recent study demonstrated that siRNA-mediated knockdown of K + channels of the Shaker (Kv1) family effectively supports the survival of axotomized RGCs. 36 This approach is substantially more specific than common, nonselective channel blockers.…”

Section: Inhibition Of Apoptotic Pathways and Manipulation Of Mitochomentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury. Gene Therapy (2012) 19, 127-136; doi:10.1038/gt.2011; published online 6 October 2011Keywords: retinal ganglion cell; neuroprotection; glaucoma NEUROPROTECTION IN GLAUCOMA: RATIONALE AND CURRENT LIMITATIONS Adult-onset glaucoma is an optic neuropathy that affects more than 50 million people around the world, with 47 million having bilateral (both eyes) blindness due to this disease. As more effective diagnostic tools become available, the number of cases is expected to rise, and a recent study predicts that there will be 70 million people with glaucoma in 2020. 1 Glaucoma is considered to be a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. The cause of glaucoma is unknown, but several risk factors have been identified, including high intraocular pressure, age and genetic predisposition. Open angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs; Figure 1) and, as these are central nervous system neurons, their loss is irreversible. At present, there is no cure for glaucoma, and the standard treatment is to lower intraocular pressure by medication or surgery. However, a significant proportion of patients continue to experience visual loss even when pharmacological treatments effectively reduce eye pressure. Therefore, novel therapeutic approaches are needed for its treatment and management.Early-onset glaucoma, comprising primary congenital glaucoma and juvenile open-angle glaucoma, has a clear genetic basis. Between 10 and 30% of individuals with juvenile open-angle glaucoma have mutations in the gene encoding myocilin, 2,3 and, on average, B40% of people with primary congenital glaucoma have mutations in the gene encoding cytochrome P450 protein. 4 Both genes are expressed in the trabecular meshwork and ciliary body, and defects in these genes may cause ocular hypertension. The elucidation of the genetic basis underlying adult-onset glaucoma is difficult because the late onset of disease limits the number of individuals available for linkage analysis. However, at least 29 genetic loci for various forms of glaucoma and 12...

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Section: Inhibition Of Apoptotic Pathways and Manipulation Of Mitochomentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

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“…The high tropism of Adeno-Associated Virus (AAV) vectors is beneficial to target RGCs, with an infection rate approaching 90% of cells near the injection site 6,7,[13][14][15] . Moreover, RGCs can be selectively transfected by applying siRNAs, plasmids, or viral vectors to the cut end of the optic nerve [16][17][18][19] or injecting vectors into their target the superior colliculus 10 . This allows researchers to study apoptotic mechanisms in the injured neuronal population without confounding effects on other bystander neurons or surrounding glia.…”

mentioning

confidence: 99%

Methods for Experimental Manipulations after Optic Nerve Transection in the Mammalian CNS

Magharious

D'Onofrio

Koeberle

2011

JoVE

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Retinal ganglion cells (RGCs) are CNS neurons that output visual information from the retina to the brain, via the optic nerve. The optic nerve can be accessed within the orbit of the eye and completely transected (axotomized), cutting the axons of the entire RGC population. Optic nerve transection is a reproducible model of apoptotic neuronal cell death in the adult CNS [1][2][3][4] . This model is particularly attractive because the vitreous chamber of the eye acts as a capsule for drug delivery to the retina, permitting experimental manipulations via intraocular injections. The diffusion of chemicals through the vitreous fluid ensures that they act upon the entire RGC population. Viral vectors, plasmids or short interfering RNAs (siRNAs) can also be delivered to the vitreous chamber in order to infect or transfect retinal cells [5][6][7][8][9][10][11][12] . The high tropism of Adeno-Associated Virus (AAV) vectors is beneficial to target RGCs, with an infection rate approaching 90% of cells near the injection site 6,7,[13][14][15] . Moreover, RGCs can be selectively transfected by applying siRNAs, plasmids, or viral vectors to the cut end of the optic nerve [16][17][18][19] or injecting vectors into their target the superior colliculus 10 . This allows researchers to study apoptotic mechanisms in the injured neuronal population without confounding effects on other bystander neurons or surrounding glia. RGC apoptosis has a characteristic time-course whereby cell death is delayed 3-4 days postaxotomy, after which the cells rapidly degenerate. This provides a window for experimental manipulations directed against pathways involved in apoptosis. Manipulations that directly target RGCs from the transected optic nerve stump are performed at the time of axotomy, immediately after cutting the nerve. In contrast, when substances are delivered via an intraocular route, they can be injected prior to surgery or within the first 3 days after surgery, preceding the initiation of apoptosis in axotomized RGCs. In the present article, we demonstrate several methods for experimental manipulations after optic nerve transection. Experiments should be carried out using aseptic technique and following the animal use protocols of your specific institution. Instruments and materials (solutions, test substances, tracers, needles, etc.) coming into contact with living tissue must be sterile to prevent infection and adverse impacts on animal welfare and potential negative impacts on the study.1. Rats will be anaesthetized using a veterinary isoflurane vaporizer system. Use medical grade oxygen at a rate of 0.8 L/min to vaporize the isoflurane gas. Place the animal in the attached anesthesia box and dial in an isoflurane concentration of 4% until the breathing has slowed and the animal is sedate. 2. Next, switch the gas flow to the gas mask attachment for the stereotaxic frame and place the animal in the stereotaxic apparatus. Turn the isoflurane concentration down to 2% and monitor anesthesia. Larger animals (>300g) may require ...

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“…It has also been shown that proapoptotic and apototic related proteins can activate voltage-gated K, Na, Ca and anion channels directly (Ekhterae et al., 2001; Koeberle et al, 2010;Platoshyn et al, 2002;Storey et al, 2003;Vander Heiden et al, 2001;Yao et al, 2011).…”

Section: Plasma Membrane-bound Voltage-gated Ion Channels Are Importamentioning

confidence: 99%

“…Altered composition of ions has been reported to directly affect activation of proteins involved in apoptosis (cytochrome c, proteases, nucleases etc), as well as formation of the apoptosome, affecting the ratio between pro-and antiapoptotic proteins Hampton et al, 1998;Hughes et al, 1997;Karki et al, 2007;Koeberle et al, 2010;Strickland et al, 1991;Thompson et al, 2001;Wondrak et al, 1991).…”

Section: Plasma Membrane-bound Voltage-gated Ion Channels Are Importamentioning

confidence: 99%

The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes

Englund¹

2014

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Apoptosis is one type of programmed cell death, important during tissue development and to maintain the tissue homeostasis. Apoptosis comprises a complex network of internal signaling pathways, and an important part of this signaling network is the action of voltage‐gated ion channels. The aim of this thesis was to explore the role of ion channels and the role of intracellular metal ions during apoptosis in Xenopus laevis oocytes. The reasons for using these oocytes are that they are large, robust, easy to handle, and easy to study electrophysiologically. Apoptosis was induced either chemically by incubation of the oocytes in staurosporine (STS) or mechanically by centrifugation of the oocytes. Ion currents were measured by a two‐electrode voltage clamp technique, intracellular ion concentrations were measured either directly by in‐house developed K+‐selective microelectrodes or indirectly by the electrophysiological technique, and apoptosis was measured by caspase‐3 activation. Paper I describes that the intracellular K+ concentration was reduced by about 30 % during STS‐induced apoptosis. However, this reduction was prevented by excessive expression of exogenous ion channels. Despite the magnitude of the intracellular K+ concentration, either normal or reduced level, the oocytes displayed normal signs of apoptosis, suggesting that the intracellular K+ reduction was not required for the apoptotic process. Because the intracellular K+ concentration was not critical for apoptosis we searched for other ion fluxes by exploring the electrophysiological properties of X. laevis oocytes. Paper II, describes a non‐inactivating Na+ current activated at positive membrane voltages that was upregulated by a factor of five during STS‐induced apoptosis. By preventing influx of Na+, the apoptotic signaling network involving capsase‐3 was prevented. To molecularly identify this voltage‐gated Na channel, the X. tropicalis genome and conserved regions of the human SCNA genes were used as a map. Paper III, shows that the voltage‐gated Na channel corresponds to the SCN2A gene ortholog and that supression of this SCN2A ortholog using miRNA prevented cell death. In conclusion, this thesis work demonstrated that a voltage‐gated Na channel is critical for the apoptotic process in X. laevis oocytes by increasing the intracellular Na+ concentration

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Kv1.1 and Kv1.3 channels contribute to the degeneration of retinal ganglion cells after optic nerve transection in vivo

Cited by 58 publications

References 36 publications

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Methods for Experimental Manipulations after Optic Nerve Transection in the Mammalian CNS

The role of ion channels and intracellular metal ions in apoptosis of Xenopus oocytes

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