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Increased ER stress as a mechanism of retinal neurovasculopathy in mice with severe hyperhomocysteinemia.

ABSTRACT: Hyperhomocysteinemia is implicated in retinal neurovascular diseases including arterial occlusive disease, venous occlusive disease and pseudoexfoliation glaucoma. The mechanism for these diseases is not known. Here we used hyperhomocysteinemic mice lacking the gene encoding cystathionine-beta-synthase (cbs-/-) to examine whether ER stress could be a mechanism for the retinal neurovasculopathy reported in these mice. Retinas of cbs+/+ and cbs-/- mice (age: 3-5 wks) were used to investigate the expression of ER stress genes (BiP/GRP78, Perk, Atf6, Atf4, Ire1?, Chop) and the proteins they encode. The levels of poly(ADP-ribose) polymerase (PARP) and cleaved cysteine-aspartic proteases-3 (caspase-3), proteins known to be involved in apoptosis, were also examined. Quantitative reverse transcription polymerase chain reaction and western blotting revealed an increase in BiP/GRP78 and PERK in retinas of cbs-/- mice compared with cbs+/+ mice. There was an elevation of CCAAT-enhancer-binding protein homologous protein (CHOP) in retinal cryosections of cbs-/- mice indicating apoptosis, which was confirmed by increased levels of PARP and cleaved caspase-3. The data suggest that the genes and proteins that are major players in the ER stress pathway, particularly the PERK pathway, are upregulated in retinas of cbs-/- mice. The data support a role for ER stress in the pathophysiology associated with the hyperhomocysteinemia-linked retinal disease.

SUBMITTER: Tawfik A

PROVIDER: S-EPMC4287205 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Increased ER stress as a mechanism of retinal neurovasculopathy in mice with severe hyperhomocysteinemia.

Tawfik Amany A Smith Sylvia B SB

Austin journal of clinical ophthalmology 20140601 5

Hyperhomocysteinemia is implicated in retinal neurovascular diseases including arterial occlusive disease, venous occlusive disease and pseudoexfoliation glaucoma. The mechanism for these diseases is not known. Here we used hyperhomocysteinemic mice lacking the gene encoding cystathionine-beta-synthase (cbs-/-) to examine whether ER stress could be a mechanism for the retinal neurovasculopathy reported in these mice. Retinas of cbs+/+ and cbs-/-</s ...[more]

PMID: 25580465

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Project description:DJ-1/PARK7 mutations or deletions cause autosomal recessive early onset Parkinson's disease (PD). Thus, DJ-1 protein has been extensively studied in brain and neurons. PD patients display visual symptoms; however, the visual symptoms specifically attributed to PD patients carrying DJ-1/PARK7 mutations are not known. In this study, we analyzed the structure and physiology of retinas of 3- and 6-month-old DJ-1 knockout (KO) mice to determine how loss of function of DJ-1 specifically contributes to the phenotypes observed in PD patients. As compared to controls, the DJ-1 KO mice displayed an increase in the amplitude of the scotopic ERG b-wave and cone ERG, while the amplitude of a subset of the dc-ERG components was decreased. The main structural changes in the DJ-1 KO retinas were found in the outer plexiform layer (OPL), photoreceptors and retinal pigment epithelium (RPE), which were observed at 3 months and progressively increased at 6 months. RPE thinning and structural changes within the OPL were observed in the retinas in DJ-1 KO mice. DJ-1 KO retinas also exhibited disorganized outer segments, central decrease in red/green cone opsin staining, decreased labeling of ezrin, broader distribution of ribeye labeling, decreased tyrosine hydroxylase in dopaminergic neurons, and increased 7,8-dihydro-8-oxoguanine-labeled DNA oxidation. Accelerated outer retinal atrophy was observed in DJ-1 KO mice after selective oxidative damage induced by a single tail vein injection of NaIO3, exposing increased susceptibility to oxidative stress. Our data indicate that DJ-1-deficient retinas exhibit signs of morphological abnormalities and physiological dysfunction in association with increased oxidative stress. Degeneration of RPE cells in association with oxidative stress is a key hallmark of age-related macular degeneration (AMD). Therefore, in addition to detailing the visual defects that occur as a result of the absence of DJ-1, our data is also relevant to AMD pathogenesis.

Dataset Information

Increased ER stress as a mechanism of retinal neurovasculopathy in mice with severe hyperhomocysteinemia.

Publications

Increased ER stress as a mechanism of retinal neurovasculopathy in mice with severe hyperhomocysteinemia.

Similar Datasets

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