TUNEL-Positive Ganglion Cells in Human Primary Open-angle Glaucoma

Kerrigan, Lisa A.; Zack, Donald J.; Quigley, Harry A.; Smith, Scott D.; Pease, Mary Ellen

doi:10.1001/archopht.1997.01100160201010

Cited by 410 publications

(255 citation statements)

References 33 publications

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“…46 Skarie and Link 92 showed that at the cellular level, loss of Wdr36 disrupts ribosomal RNA maturation and leads to nucleolar morphology defects, resulting in activation of the p53 stress-response pathway. In POAG, it is established that RGCs are lost because of apoptosis 93,94 and p53 is a key regulator of the apoptotic pathway. Their data showing an interaction of p53 and WDR36 suggest that variants in these genes could potentially synergize in POAG pathogenesis.…”

Section: Wdr36 At the Glc1g Locusmentioning

confidence: 99%

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Gemenetzi

Yang

Lotery

2011

Eye

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Section: Wdr36 At the Glc1g Locusmentioning

confidence: 99%

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Gemenetzi

Yang

Lotery

2011

Eye

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“…Presumably IOP disrupts the function of RGC axons by increasing mechanical forces on the lamina cribrosa of the optic nerve head (ONH). Although exact underlying mechanisms that link elevated IOP to glaucomatous RGC death are not completely understood, RGC apoptosis is considered an important step leading to glaucoma development [2][3][4]. Whatever are the primary and secondary factors inducing apoptosis, the end result in glaucomatous eyes is the dysfunction and death of RGCs.…”

Section: Introductionmentioning

confidence: 99%

Matrix metalloproteinase 9 expression: new regulatory elements

Surgucheva

Chidambaram

Willoughby

et al. 2010

j ocul biol dis inform

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Retinal ganglion cells apoptosis is linked to matrix metalloproteinase 9 (MMP-9) controlled changes of extracellular matrix. Abnormal expression of MMP-9 is associated with glaucomatous alterations. Thus, the knowledge of MMP-9 regulation is important for the understanding the pathogenesis of glaucoma. Here, we investigated the role of 3′-untranslated regions (3′-UTR) and microRNAs in MMP-9 regulation. We used in vitro mutagenesis and Luc reporter system to identify regulatory elements in the 3′-UTR of MMP-9. microRNAs were analyzed by qRT-PCR, and their role was investigated with inhibitors and mimics. We identified targets for miRNAs in 3′-UTR of MMP-9 involved in the regulation of MMP-9 expression. We then isolated miRNAs from the optic nerve A7 astrocytes and 293 T cells and confirmed the role of mi340 in the regulation using specific inhibitors and mimics. The results obtained show a new miRNA-mediated mechanism of MMP-9 expression regulation.

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“…Although the triggers of RGC death are not clear, they have been shown to die by apoptosis in both animal models (4-6) and human disease (7,8). Activation of two initiator caspase pathways, caspase 8 (9, 10) and caspase 9 (5, 9), has been reported in experimental glaucoma.…”

mentioning

confidence: 99%

Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma

Huang

Fileta

Dobberfuhl

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

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Increased intraocular pressure (IOP) leads, by an unknown mechanism, to apoptotic retinal ganglion cell (RGC) death in glaucoma. We now report cleavage of the autoinhibitory domain of the protein phosphatase calcineurin (CaN) in two rodent models of increased IOP. Cleaved CaN was not detected in rat or mouse eyes with normal IOP. In in vitro systems, this constitutively active cleaved form of CaN has been reported to lead to apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member, Bad. In a rat model of glaucoma, we similarly detect increased Bad dephosphorylation, increased cytoplasmic cytochrome c (cyt c), and RGC death. Oral treatment of rats with increased IOP with the CaN inhibitor FK506 led to a reduction in Bad dephosphorylation and cyt c release. In accord with these biochemical results, we observed a marked increase in both RGC survival and optic nerve preservation. These data are consistent with a CaN-mediated mechanism of increased IOP toxicity. CaN cleavage was not observed at any time after optic nerve crush, suggesting that axon damage alone is insufficient to trigger cleavage. These findings implicate this mechanism of CaN activation in a chronic neurodegenerative disease. These data demonstrate that increased IOP leads to the initiation of a CaN-mediated mitochondrial apoptotic pathway in glaucoma and support neuroprotective strategies for this blinding disease.retina ͉ optic nerve ͉ apoptosis

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TUNEL-Positive Ganglion Cells in Human Primary Open-angle Glaucoma

Cited by 410 publications

References 33 publications

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Matrix metalloproteinase 9 expression: new regulatory elements

Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental glaucoma

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