Autophagic dysregulation in glaucomatous trabecular meshwork cells

Porter, Kristine; Hirt, Joshua; Stamer, W. Daniel; Liton, Paloma B.

doi:10.1016/j.bbadis.2014.11.021

Cited by 67 publications

(61 citation statements)

References 40 publications

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“…In a recent work, our laboratory reported the dysregulation of autophagy with aging and in TM cells isolated from glaucoma cadaver eyes 17 . A connection between autophagy and neurodegeneration in glaucoma is strongly supported from the discovery that the optineurin and TANK Binding Kinase (TBK1), normal tension glaucoma (NTG)-associated genes, are essential players in the autophagic degradation of damaged mitochondria, a process known as mitophagy 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model

et al. 2018

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Glaucoma is a progressive optic neuropathy characterized by axonal degeneration and retinal ganglion cells loss. Several factors have been postulated to play a role in glaucoma, elevated intraocular pressure (IOP) being the best well-known causative factor. The mechanisms leading to ocular hypertension and glaucoma are still not fully understood. An increasing number of evidence indicates a role of autophagy in the pathophysiological process of ocular hypertension and glaucoma. However, while all of the studies agree that autophagy is induced in RGCs in response to injury, autophagy was found to either protect or promote cell death depending on the experimental model used. In order to gain more insight into both, the role of autophagy in the pathogenesis of glaucoma and the effect of chronic IOP elevation in the autophagy pathway, we have investigated here for the first time autophagy in the iridocorneal angle region, retinal ganglion cell bodies, and ON axons in the spontaneous ocular hypertensive DBA/2J mouse glaucoma model and in the transgenic DBA/2J::GFP-LC3 mice, generated in our laboratory. Our results indicate decreased autophagic flux in the outflow pathway cells in the DBA/2J mice, characterized by increased levels of LC3-II and p62 together with a decrease in the lysosomal marker LAMP1, evaluated by western blot and immunofluorescence. Elevated presence of autophagic vacuoles in the DBA/2J and, in particular, in the DBA/2J::GFP-LC3 mice was also observed. Expression of the GFP-LC3 transgene was associated to higher cumulative IOP in the DBA/2J background. In addition to higher elevation in IOP, DBA/2J::GFP-LC3 were characterized by further RGCs and exacerbated axonal degeneration compared to DBA/2J. This was accompanied by the notable high presence of autophagic figures within degenerating axons. These results strongly suggest overactivation of autophagy as a potential cellular mechanism leading to ON degeneration in the chronic hypertensive DBA/2J mice.

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Section: Introductionmentioning

confidence: 99%

Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model

et al. 2018

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“…Activation of autophagy represents an essential mechanism by which organisms can repair stress-induced damage and adapt to the new environmental conditions. Dysfunction in the autophagy pathway has been associated with several human diseases, including glaucoma (Levine and Kroemer, 2008; Porter et al, 2015). …”

Section: Autophagy: a Stress Response Adaptive Pathwaymentioning

confidence: 99%

“…First indirect evidence come from older studies describing increased hydrolase activities in the TM of glaucomatous eyes (Coupland et al, 1993), as well as ultrastructural changes, such as the presence of membrane-limited vesicles filled with granular material and accumulation of autophagic vacuoles and pigment granules in the cytoplasm of glaucomatous TM cells (Cracknell et al, 2006; Rohen, 1982; Tektas and Lütjen-Drecoll, 2009). More direct experimental evidence linking autophagy to outflow pathway pathophysiology comes from our latest study, in which we evaluated autophagic lysosomal function in TM cells isolated from glaucomatous donors and compared it to that in age-matched donor eyes (Porter et al, 2015). Glaucomatous TM cells displayed a significant decrease in the steady-state levels of LC3-II, reduced lysosomal proteolysis, and chronic activation of the mTOR autophagy inhibitory pathway, indicating that autophagy was constitutively suppressed in these cultures.…”

Section: Dysregulation Of Autophagy With Oxidative Stress and In Tmentioning

confidence: 99%

Autophagy and mechanotransduction in outflow pathway cells

Hirt

Liton

2017

Experimental Eye Research

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Because of elevations in IOP and other forces, cells in the trabecular meshwork (TM) are constantly subjected to mechanical strain. In order to preserve cellular function and regain homeostasis, cells must sense and adapt to these morphological changes. We and others have already shown that mechanical stress can trigger a broad range of responses in TM cells; however, very little is known about the strategies that TM cells use to respond to this stress, so they can adapt and survive. Autophagy, a lysosomal degradation pathway, has emerged as an important cellular homeostatic mechanism promoting cell survival and adaptation to a number of cytotoxic stresses. Our laboratory has reported the activation of autophagy in TM cells in response to static biaxial strain and high pressure. Moreover, our newest data also suggest the activation of chaperon-assisted selective autophagy, a recently identified tension-induced autophagy essential for mechanotransduction, in TM cells under cyclic mechanical stress. In this review manuscript we will discuss autophagy as part of an integrated response triggered in TM cells in response to strain, exerting a dual role in repair and mechanotransduction, and the potential effects of dysregulated in outflow pathway pathophysiology.

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“…These include elastin, fibronectin, glycoprotein 39, TIMP-2, MMP-1, -3 and -10, carboxy glutamic acid (GLA), cochlin, myocilin, periostin, TSP-3, collagen I, III, V, VI, XI, XII, and XIV. (Acott and Kelley, 2008; Liton et al, 2006) Besides, TM cells exposed to hyperoxic culture conditions or treated with hydrogen peroxide display autophagic dysfunction (Porter et al, 2015), plus activation of the protein kinase B (Akt), p38, and extracellular regulated kinase (ERK) 1/2 signaling pathways(Awai-Kasaoka et al, 2013). …”

Section: Similarities Between Lc and Jct Cells Related To Glaucomamentioning

confidence: 99%

Life under pressure: The role of ocular cribriform cells in preventing glaucoma

Paula

O’Brien

Stamer

2016

Experimental Eye Research

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Primary open-angle glaucoma is a multifactorial blinding disease often impacting the two pressure-sensitive regions of the eye: the conventional outflow pathway and the optic nerve head (ONH). The connective tissues that span these two openings in the globe are the trabecular meshwork of the conventional outflow pathway and the lamina cribrosa of the ONH. Resident cribiform cells of these two regions are responsible for actively remodeling and maintaining their connective tissues. In glaucoma, aberrant maintenance of the juxtacanalicular tissues (JCT) of the conventional outflow pathway results in ocular hypertension and pathological remodeling of the lamina cribrosa results in ONH cupping, damaging retinal ganglion cell axons. Interestingly, cells cultured from the lamina cribrosa and the JCT of the trabecular meshwork have similarities regarding gene expression, protein production, plus cellular responses to growth factors and mechanical stimuli. This review compares and contrasts the current knowledge of these two cell types, whose health is critical for protecting the eye from glaucomatous changes. In response to pressure gradients across their respective cribiform tissues, the goal is to better understand and differentiate healthy from pathological behavior of these two cell types.

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Autophagic dysregulation in glaucomatous trabecular meshwork cells

Cited by 67 publications

References 40 publications

Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model

Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model

Autophagy and mechanotransduction in outflow pathway cells

Life under pressure: The role of ocular cribriform cells in preventing glaucoma

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