Ocular manifestation of storage diseases

Biswas, Jyotirmay; Nandi, Krishnendu; Sridharan, Sridha; Ranjan, Prabhat

doi:10.1097/icu.0b013e32831215c3

Cited by 20 publications

(18 citation statements)

References 35 publications

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“…The higher number of autolysosomes and the increased presence of cargo material within them, while keeping the same cellular degradative capacity, might result in the accumulation of undegraded material within residual bodies and compromise cellular components turnover and cell function. Very importantly, a pathological effect of the intralysosomal accumulation of substances in TM tissue physiology is highlighted by the observation that ocular hypertension and glaucoma are clinical manifestations associated with a number of lysosomal storage disorders, including Hurler Disease, Morquio syndrome and Maroteaux–Lamy syndrome 48 , 49 …”

Section: Resultsmentioning

confidence: 99%

Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells

Porter

Jeyabalan²,

Lin³

et al. 2013

Autophagy

103

100

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Increasing evidence suggests oxidative damage as a key factor contributing to the failure of the conventional outflow pathway tissue to maintain appropriate levels of intraocular pressure, and thus increase the risk for developing glaucoma, a late-onset disease which is the second leading cause of permanent blindness worldwide. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors, including oxidative stress. Here, we have monitored, by using different methodologies (LC3-I to LC3-II turnover, tfLC3, and Cyto ID), the induction of autophagy and autophagy flux in TM cells subjected to a normobaric hyperoxic model of mild chronic oxidative stress. Our data indicate the MTOR-mediated activation of autophagy and nuclear translocation of TFEB in oxidatively stressed TM cells, as well as the role of autophagy in the occurrence of SA-GLB1/SA-β-gal. Concomitant with the activation of the autophagic pathway, TM cells grown under oxidative stress conditions displayed, however, reduced cathepsin (CTS) activities, reduced lysosomal acidification and impaired CTSB proteolytic maturation, resulting in decreased autophagic flux. We propose that diminished autophagic flux induced by oxidative stress might represent one of the factors leading to progressive failure of cellular TM function with age and contribute to the pathogenesis of primary open angle glaucoma.

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Section: Resultsmentioning

confidence: 99%

Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells

Porter

Jeyabalan²,

Lin³

et al. 2013

Autophagy

103

100

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“…A recent work by Keller et al also provides a genetic link between autophagy and glaucoma since ASB10, a novel candidate POAG gene, was shown to participate in ubiquitin-mediated degradation pathways (Keller et al, 2013). The importance of autophagy in outflow physiology is additionally supported by the observation that ocular hypertension is an ocular manifestation described in patients with lysosomal storage disorders (Biswas et al, 2008; Nowaczyk et al, 1988; Spellacy et al, 1980). …”

Section: Autophagy In Outflow Pathway Pathophysiology: Implicationmentioning

confidence: 90%

The autophagic lysosomal system in outflow pathway physiology and pathophysiology

Liton

2016

Experimental Eye Research

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Malfunction of the trabecular meshwork (TM)/schlemm’s canal (SC) conventional outflow pathway is associated with elevated intraocular pressure (IOP) and, therefore, increased risk of developing glaucoma, a potentially blinding disease affecting more than 70 million people worldwide. This TM/SC tissue is subjected to different types of stress, including mechanical, oxidative, and phagocytic stress. Long-term exposure to these stresses is believed to lead to a progressive accumulation of damaged cellular and tissue structures causing permanent alterations in the tissue physiology, and contribute to the pathologic increase in aqueous humor (AH) outflow resistance. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors. In addition to performing basal functions, autophagy acts as a cellular survival pathway and represents an essential mechanism by which organisms can adapt to acute stress conditions and repair stress-induced damage. A decline in autophagy has been observed in most tissues with aging and has been considered responsible, at least in part, for the accumulation of damaged cellular components in almost all tissues of aging organisms. Dysfunction in the autophagy pathway is associated with several human diseases, from infectious diseases to cancer and neurodegeneration. In this review, we will summarize our current knowledge of the emerging roles of autophagy in outflow tissue physiology and pathophysiology, including novel evidence suggesting compromised autophagy in the glaucomatous outflow pathway.

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“…Nevertheless, the ocular involvement can alternatively reflect other more generalized defects in LSDs [35]. Keeping in mind the evidence that in vivo CLSM allows the early recognition of morphological changes in the cornea during the progression of disease or treatment course, we believe that this technique has the potential to become an additional clinical tool for reliable diagnosis and evaluation of treatment options in NPC1 disorder.…”

Section: Discussionmentioning

confidence: 97%

“…The deficit in SEM occurs both in vertical and horizontal plane. Another sign of NPC1 disease addressing to ocular involvement is the macular cherry red spot, which is one of most important symptoms in the diagnosis of almost all storage diseases [34], [35]. The corneal involvement in NPC1 disease has been only seldom reported, and even these rare data are inconsistent, reporting in one case on corneal inclusions [36] and in another case on normal corneal morphology without any abnormalities [37], even though the same techniques (histology and electron microscopy) were used in both studies.…”

Section: Discussionmentioning

confidence: 99%

Corneal Alterations during Combined Therapy with Cyclodextrin/Allopregnanolone and Miglustat in a Knock-Out Mouse Model of NPC1 Disease

et al. 2011

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BackgroundNiemann Pick disease type C1 is a neurodegenerative disease caused by mutations in the NPC1 gene, which result in accumulation of unesterified cholesterol and glycosphingolipids in the endosomal-lysosomal system as well as limiting membranes. We have previously shown the corneal involvement in NPC1 pathology in form of intracellular inclusions in epithelial cells and keratocytes. The purpose of the present study was to clarify if these inclusions regress during combined substrate reduction- and by-product therapy (SRT and BPT).Methodology/Principal FindingsStarting at postnatal day 7 (P7) and thereafter, NPC1 knock-out mice (NPC1−/−) and wild type controls (NPC1+/+) were injected with cyclodextrin/allopregnanolone weekly. Additionally, a daily miglustat injection started at P10 until P23. Starting at P23 the mice were fed powdered chow with daily addition of miglustat. The sham group was injected with 0.9% NaCl at P7, thereafter daily starting at P10 until P23, and fed powdered chow starting at P23. For corneal examination, in vivo confocal laser-scanning microscopy (CLSM) was performed one day before experiment was terminated. Excised corneas were harvested for lipid analysis (HPLC/MS) and electron microscopy.In vivo CLSM demonstrated a regression of hyperreflective inclusions in all treated NPC1−/−mice. The findings varied between individual mice, demonstrating a regression, ranging from complete absence to pronounced depositions. The reflectivity of inclusions, however, was significantly lower when compared to untreated and sham-injected NPC1−/− mice. These confocal findings were confirmed by lipid analysis and electron microscopy. Another important CLSM finding revealed a distinct increase of mature dendritic cell number in corneas of all treated mice (NPC1−/− and NPC1+/+), including sham-treated ones.Conclusions/SignificanceThe combined substrate reduction- and by-product therapy revealed beneficial effects on the cornea. In vivo CLSM is a non-invasive tool to monitor disease progression and treatment effects in NPC1 disorder.

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Ocular manifestation of storage diseases

Abstract: The majority of these patients have poor vision due to various ocular complications that are often very difficult to monitor and treat.

Cited by 20 publications

References 35 publications

Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells

Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells

The autophagic lysosomal system in outflow pathway physiology and pathophysiology

Corneal Alterations during Combined Therapy with Cyclodextrin/Allopregnanolone and Miglustat in a Knock-Out Mouse Model of NPC1 Disease

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