A Glaucoma-Associated Mutant of Optineurin Selectively Induces Death of Retinal Ganglion Cells Which Is Inhibited by Antioxidants

Chalasani, Madhavi Latha Somaraju; Radha, Vegesna; Gupta, Vijay; Agarwal, Neeraj; Balasubramanian, D.; Swarup, Ghanshyam

doi:10.1167/iovs.06-0834

Cited by 104 publications

(111 citation statements)

References 25 publications

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“…E50K is a dominant mutation that causes glaucoma by directly inducing the death of retinal ganglion cells (Chalasani et al, 2007;Chi et al, 2010). Upon overexpression, E50K-optineurin inhibits endocytic trafficking of TfR, resulting in accumulation of TfR in large E50K-positive structures or foci (Nagabhushana et al, 2010;Park et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Point mutations in TBC1D17 were created by a PCR-based site-directed mutagenesis strategy following the protocol described in QuikChangeH site-directed mutagenesis kit (Stratagene, La Jolla, CA, USA). Plasmid vectors for expressing human optineurin and its mutant (E50K) with a HA and GFP tag have been described previously (Chalasani et al, 2007;Nagabhushana et al, 2010). A GST fusion protein of optineurin was made by subcloning it in pGEX-5X2 vector (GE Healthcare, Uppsala, Sweden).…”

Section: Methodsmentioning

confidence: 99%

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Optineurin mediates negative regulation of Rab8 function by TBC1D17, a GTPase activating protein

Vaibhava

Nagabhushana

Chalasani

et al. 2012

Journal of Cell Science

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SummaryRab GTPases regulate various membrane trafficking pathways but the mechanisms by which GTPase-activating proteins recognise specific Rabs are not clear. Rab8 is involved in controlling several trafficking processes, including the trafficking of transferrin receptor from the early endosome to the recycling endosome. Here, we provide evidence to show that TBC1D17, a Rab GTPase-activating protein, through its catalytic activity, regulates Rab8-mediated endocytic trafficking of transferrin receptor. Optineurin, a Rab8-binding effector protein, mediates the interaction and colocalisation of TBC1D17 with Rab8. A non-catalytic region of TBC1D17 is required for direct interaction with optineurin. Co-expression of Rab8, but not other Rabs tested, rescues the inhibition of transferrin receptor trafficking by TBC1D17. The activated GTP-bound form of Rab8 is localised to the tubules emanating from the endocytic recycling compartment. Through its catalytic activity, TBC1D17 inhibits recruitment of Rab8 to the tubules and reduces colocalisation of transferrin receptor and Rab8. Knockdown of optineurin or TBC1D17 results in enhanced recruitment of Rab8 to the tubules. A glaucoma-associated mutant of optineurin, E50K, causes enhanced inhibition of Rab8 by TBC1D17, resulting in defective endocytic recycling of transferrin receptor. Our results show that TBC1D17, through its interaction with optineurin, regulates Rab8-mediated endocytic recycling of transferrin receptor and recruitment of Rab8 to the endocytic recycling tubules. We describe a mechanism of regulating a Rab GTPase by an effector protein (optineurin) that acts as an adaptor to bring together a Rab (Rab8) and its GTPase-activating protein (TBC1D17).

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Optineurin mediates negative regulation of Rab8 function by TBC1D17, a GTPase activating protein

Vaibhava

Nagabhushana

Chalasani

et al. 2012

Journal of Cell Science

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“…However, a mutated form of optineurin, E50K, identified in normal-tension glaucoma patients, loses its ability to translocate to the nucleus and when over-expressed compromises the mitochondrial membrane integrity, resulting in cells that are less fit to survive under stress conditions (De Marco et al, 2006). In a recent study, a glaucoma-associated mutant of optineurin has been shown to selectively induce oxidative stress-mediated RGC death, and optineurin has been suggested to be a likely component of the TNF-α signaling pathway leading to RGC death (Chalasani et al, 2007). More recently, microRNA silencing of optineurin has resulted in markedly enhanced TNF-α-induced nuclear factor kappaB (NF-KB) activity, thereby supporting a physiologic role of optineurin in dampening TNF-α signaling in association with glaucoma (Zhu et al, 2007).…”

Section: Evidence Supporting the Role Of Tnf-α As A Mediator Of Retinmentioning

confidence: 99%

TNF-α signaling in glaucomatous neurodegeneration

Tezel

2008

Progress in Brain Research

231

190

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Growing evidence supports the role of TNF-α as a mediator of neurodegeneration in glaucoma. Glial production of TNF-α is increased and its death receptor is up-regulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. Opposing these cell-death promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-α as best exemplified by differential responses of RGCs and glia. In addition to the direct neurotoxicity of TNF-α to RGCs and their axons, potential interplay of TNF-α signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to secondary neurodegenerative injury. This review focuses on the present evidence supporting the involvement of TNF-α signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.

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“…(28)(29)(30) Optineurin may possibly influence ganglion cell apoptosis directly through rab8 signaling. (31,32) WD repeat domain 36 (WDR36) at GLC1G (5q21.3-q22.1) seems to be related to POAG severity in some cases, although it is neither necessary nor sufficient for disease development. (33,34) A zebrafish homolog of WDR36 stimulates apoptosis mediated by p53, implying a possible role for the gene in retinal ganglion cell susceptibility to apoptotic cell death.…”

Section: Genetic Biomarkersmentioning

confidence: 99%

Biomarkers and surrogate endpoints in the glaucomatous optic neuropathy: new developments and a review

Kasahara¹

2015

Revista Brasileira De Oftalmologia

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Glaucoma is a group of progressive optic neuropathies that have in common a slow progressive degeneration of retinal ganglion cells and their axons, resulting in a distinct RESUMOO glaucoma compreende um grupo de neuropatias ópticas progressivas que tem em comum a degeneração lenta e progressiva das células ganglionares e seus axônios, resultando em aparência única do disco óptico e, simultaneamente, um padrão correspondente de perda visual. Biomarcadores são características medidas objetivamente e avaliadas como indicadores de processo biológico normal, processos patológicos ou respostas farmacológicas à uma intervenção terapêutica. Vários marcadores biológicos foram associados com glaucoma, especialmente os genéticos, proteômicos, autoimunes e outros biomarcadores moleculares, embora a maioria ainda necessite de validação clínica. Existem potenciais benefícios em usar biomarcadores. Informações podem ser obtidas mais precocemente, de forma mais rápida e menos onerosa. Esta revisão resume os últimos avanços e métodos em biomarcadores de glaucoma e seu possível uso no diagnóstico, estadiamento e como preditores da resposta ao tratamento.

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A Glaucoma-Associated Mutant of Optineurin Selectively Induces Death of Retinal Ganglion Cells Which Is Inhibited by Antioxidants

Abstract: The E50K mutation of optineurin acquired the ability to induce cell death selectively in retinal ganglion cells. This cell death was mediated by oxidative stress. The present findings raise the possibility of antioxidant use for delaying or controlling some forms of glaucoma.

Cited by 104 publications

References 25 publications

Optineurin mediates negative regulation of Rab8 function by TBC1D17, a GTPase activating protein

Optineurin mediates negative regulation of Rab8 function by TBC1D17, a GTPase activating protein

TNF-α signaling in glaucomatous neurodegeneration

Biomarkers and surrogate endpoints in the glaucomatous optic neuropathy: new developments and a review

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