Expression of Myocilin Mutants Sensitizes Cells to Oxidative Stress-Induced Apoptosis

Margetis, Joe; Tomarev, Stanislav I.

doi:10.2353/ajpath.2010.090853

Cited by 56 publications

(62 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cultures of pTM (27) were infected with adenoviral vectors expressing the same myocilin construct as in the transgenic mice (Ad5RSV-myocilin Y437H ). Expression of this mutated protein has been reported to result in cellular stress and reduced cell survival (35)(36)(37).…”

Section: Resultsmentioning

confidence: 99%

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Zhu

Gramlich

Laboissonniere

et al. 2016

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

133

View full text Add to dashboard Cite

Glaucoma is a common cause of vision loss or blindness and reduction of intraocular pressure (IOP) has been proven beneficial in a large fraction of glaucoma patients. The IOP is maintained by the trabecular meshwork (TM) and the elevation of IOP in open-angle glaucoma is associated with dysfunction and loss of the postmitotic cells residing within this tissue. To determine if IOP control can be maintained by replacing lost TM cells, we transplanted TM-like cells derived from induced pluripotent stem cells into the anterior chamber of a transgenic mouse model of glaucoma. Transplantation led to significantly reduced IOP and improved aqueous humor outflow facility, which was sustained for at least 9 wk. The ability to maintain normal IOP engendered survival of retinal ganglion cells, whose loss is ultimately the cause for reduced vision in glaucoma. In vivo and in vitro analyses demonstrated higher TM cellularity in treated mice compared with littermate controls and indicated that this increase is primarily because of a proliferative response of endogenous TM cells. Thus, our study provides in vivo demonstration that regeneration of the glaucomatous TM is possible and points toward novel approaches in the treatment of this disease.G laucoma is one of the most common causes of irreversible vision loss and blindness worldwide; ∼60 million suffer from this disease, and of these, 7 million are blind (1). By definition all glaucoma involves some degree of vision loss, which is because of the death of retinal ganglion cells (RGC), as well as degeneration of the optic nerve head, the optic nerve, and the lateral geniculate nucleus (2, 3). Advanced age and elevated intraocular pressure (IOP) are the two most significant risk factors for the development of glaucoma. Elevated IOP is typically a result of disturbances in the balance of aqueous humor production and drainage. Aqueous humor is continuously synthesized within the eye and drained primarily through the trabecular meshwork (TM), a specialized structure located anterior to the root of the iris. Although occlusion of the aqueous humor outflow pathways can occur through several mechanisms, in the United States and other Western populations the most common form of glaucoma is primary open angle glaucoma (POAG), which manifests no gross abnormalities to the anterior portion of the eye.Randomized clinical trials have shown that reduction of IOP slows the onset and progression of glaucoma, even in patients without suspicious elevation of IOP (4, 5). Although there has been increasing awareness that factors other than elevated IOP contribute to glaucomatous damage, to date all treatments for glaucoma remain aimed at reducing IOP either through surgical or medical means, which has resulted in significant preservation of vision and increased quality of life for millions of glaucoma patients (6, 7).Although the TM in eyes with POAG appears relatively normal at a gross morphological level, a number of more subtle changes influencing the mechanical properties of the TM collage...

show abstract

Section: Resultsmentioning

confidence: 99%

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Zhu

Gramlich

Laboissonniere

et al. 2016

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

133

View full text Add to dashboard Cite

show abstract

“…cause disease, it remains unknown why the aggregation of myocilin intracellularly results in elevated IOP; however, recent work suggests that accumulation of myocilin aggregates intracellularly may sensitize trabecular meshwork cells to apoptosis (55).…”

Section: Figurementioning

confidence: 99%

Glaucoma: genes, phenotypes, and new directions for therapy

Fan

Wiggs²

2010

J. Clin. Invest.

124

View full text Add to dashboard Cite

Glaucoma, a leading cause of blindness worldwide, is characterized by progressive optic nerve damage, usually associated with intraocular pressure. Although the clinical progression of the disease is well defined, the molecular events responsible for glaucoma are currently poorly understood and current therapeutic strategies are not curative. This review summarizes the human genetics and genomic approaches that have shed light on the complex inheritance of glaucoma genes and the potential for gene-based and cellular therapies that this research makes possible.

show abstract

“…(26) The absence of protein does not cause disease, however, intracellular accumulation of myocilin aggregates may sensitize trabecular meshwork cells to apoptosis. (27) The second gene optineurin (OPTN) was identified at GLC1E (10p15-p14) and is primarily responsible for rare cases of familial normal tension glaucoma. (28)(29)(30) Optineurin may possibly influence ganglion cell apoptosis directly through rab8 signaling.…”

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

View full text Add to dashboard Cite

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.

show abstract

Expression of Myocilin Mutants Sensitizes Cells to Oxidative Stress-Induced Apoptosis

Cited by 56 publications

References 53 publications

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

Glaucoma: genes, phenotypes, and new directions for therapy

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

Contact Info

Product

Resources

About