Proteomics Analysis of Molecular Risk Factors in the Ocular Hypertensive Human Retina

Yang, Xiangjun; Hondur, Gözde; Li, Ming; Cai, Jian; Klein, Jon B.; Kuehn, Markus H.; Tezel, Gülgün

doi:10.1167/iovs.15-17294

Cited by 39 publications

(28 citation statements)

References 81 publications

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“…Moreover, retinas from DBA/2J mice aged 12 to 14 months exhibited a significant reduction in the steady-state levels of mitochondrial proteins involved in energetic metabolism, organelle dynamics, or antioxidant defenses. Proteomic studies investigating human retina samples from glaucomatous or ocular hypertensive patients established that an array of mitochondrial proteins displayed significant level reductions 47, 48. Consequently, insufficiency in the energy supply could initiate defects in electrical conduction and axonal transport, thereby leading to neuronal cell loss and, ultimately, glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Neuroglobin Can Prevent or Reverse Glaucomatous Progression in DBA/2J Mice

Cwerman-Thibault

Lechauve

Augustin

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Mitochondrial dysfunction is responsible for hereditary optic neuropathies. We wished to determine whether preserving mitochondrial bioenergetics could prevent optic neuropathy in a reliable model of glaucoma. DBA/2J mice exhibit elevated intraocular pressure, progressive degeneration of their retinal ganglion cells, and optic neuropathy that resembles glaucoma. We established that glaucoma in these mice is directly associated with mitochondrial dysfunction: respiratory chain activity was compromised in optic nerves 5 months before neuronal loss began, and the amounts of some mitochondrial proteins were reduced in retinas of glaucomatous mice. One of these proteins is neuroglobin, which has a neuroprotective function. Therefore, we investigated whether gene therapy aimed at restoring neuroglobin levels in the retina via ocular administration of an adeno-associated viral vector could reduce neuronal degeneration. The approach of treating 2-month-old mice impeded glaucoma development: few neurons died and respiratory chain activity and visual cortex activity were comparable to those in young, asymptomatic mice. When the treatment was performed in 8-month-old mice, the surviving neurons acquired new morphologic and functional properties, leading to the preservation of visual cortex activity and respiratory chain activity. The beneficial effects of neuroglobin in DBA/2J retinas confirm this protein to be a promising candidate for treating glaucoma.

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Section: Discussionmentioning

confidence: 99%

Neuroglobin Can Prevent or Reverse Glaucomatous Progression in DBA/2J Mice

Cwerman-Thibault

Lechauve

Augustin

et al. 2017

Molecular Therapy - Methods & Clinical Development

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“…This may be particularly detrimental for non-dividing cells such as those in the TM and the retina since the accumulated material would not be diluted by distribution to daughter cells. A recent proteomics study showed many proteins linked to the ubiquitination pathway are up-regulated in hypertensive human retinas (Yang et al, 2015b). Interestingly, two up-regulated proteins identified in this hypertensive study, HSPB1 and UBC, were identified to bind to ASB10 (Andresen et al, 2014).…”

Section: Asb10 Expression and Functionmentioning

confidence: 99%

Working your SOCS off: The role of ASB10 and protein degradation pathways in glaucoma

Keller

Wirtz

2017

Experimental Eye Research

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Evidence is accumulating to suggest that mutations in the Ankyrin and SOCS Box-containing protein-10 (ASB10) gene are associated with glaucoma. Since its identification in a large Oregon family with primary open-angle glaucoma (POAG), ASB10 variants have been associated with disease in US, German and Pakistani cohorts. ASB10 is a member of the ASB family of proteins, which have a common structure including a unique N-terminus, a variable number of central ankyrin (ANK) repeat domains and a suppressor of cytokine signaling (SOCS) box at the C-terminus. Mutations in ASB10 are distributed throughout the entire length of the gene including the two alternatively spliced variants of exon 1. A homozygous mutation in a Pakistani individual with POAG, which lies in the center of the SOCS box, is associated with a particularly severe form of the disease. Like other SOCS box-containing proteins, ASB10 functions in ubiquitin-mediated degradation pathways. The ANK repeats bind to proteins destined for degradation. The SOCS box recruits ubiquitin ligase proteins to form a complex to transfer ubiquitin to a substrate bound to the ANK repeats. The ubiquitin-tagged protein then enters either the proteasomal degradation pathway or the autophagic-lysosomal pathway. The choice of pathway appears to be dependent on which lysine residues are used to build polyubiquitin chains. However, these reciprocal pathways work in tandem to degrade proteins because inhibition of one pathway increases degradation via the other pathway. In this publication, we will review the literature that supports identification of ASB10 as a glaucoma-associated gene and the current knowledge of the function of the ASB10 protein. In addition, we present new data that indicates ASB10 expression is up-regulated by the inflammatory cytokines tumor necrosis factor-α and interleukin-1α. Finally, we will describe the emerging role of other SOCS box-containing proteins in protein degradation pathways in ocular cells.

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“…The longer the injury lasts or the more dramatically increased the IOP is, the greater the extent of the immediate increase in autophagy is, inducing RGC death in a relatively short period of time [105]. Additionally, various proteins involved in cellular redox homeostasis and the OS response were upregulated in the retinas of ocular hypertensive humans [106]. In a retinal ischemia-reperfusion (I/R) model, the loss of neurons in the RGC layer was more severe in Nrf2 KO mice than in wild-type mice, and the RGC activity of Nrf2 KO mice was reduced, indicating that Nrf2 had an inherent protective effect in RGCs [107].…”

Section: Fuchs' Endothelial Corneal Dystrophy (Fecd)mentioning

confidence: 99%

Potential Protective and Therapeutic Roles of the Nrf2 Pathway in Ocular Diseases: An Update

Wang

Zhao

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nuclear factor- (erythroid-derived 2-) like 2 (Nrf2) is a regulator of many processes of life, and it plays an important role in antioxidant, anti-inflammatory, and antifibrotic responses and in cancer. This review is focused on the potential mechanism of Nrf2 in the occurrence and development of ocular diseases. Also, several Nrf2 inducers, including noncoding RNAs and exogenous compounds, which control the expression of Nrf2 through different pathways, are discussed in ocular disease models and ocular cells, protecting them from dysfunctional changes. Therefore, Nrf2 might be a potential target of protecting ocular cells from various stresses and preventing ocular diseases.

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Proteomics Analysis of Molecular Risk Factors in the Ocular Hypertensive Human Retina

Cited by 39 publications

References 81 publications

Neuroglobin Can Prevent or Reverse Glaucomatous Progression in DBA/2J Mice

Neuroglobin Can Prevent or Reverse Glaucomatous Progression in DBA/2J Mice

Working your SOCS off: The role of ASB10 and protein degradation pathways in glaucoma

Potential Protective and Therapeutic Roles of the Nrf2 Pathway in Ocular Diseases: An Update

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