May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Activation of the Unfolded Protein Response in the Lens Inhibits General Protein Translation Resulting in Altered Fiber Cell Differentiation and Cataract
Author Affiliations & Notes
  • Z. Firtina
    Biological Sciences, Univ of Delaware, Newark, Delaware
  • B. P. Danysh
    Biological Sciences, Univ of Delaware, Newark, Delaware
  • M. K. Duncan
    Biological Sciences, Univ of Delaware, Newark, Delaware
  • Footnotes
    Commercial Relationships  Z. Firtina, None; B.P. Danysh, None; M.K. Duncan, None.
  • Footnotes
    Support  NIE EY015279
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3255. doi:https://doi.org/
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      Z. Firtina, B. P. Danysh, M. K. Duncan; Activation of the Unfolded Protein Response in the Lens Inhibits General Protein Translation Resulting in Altered Fiber Cell Differentiation and Cataract. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3255. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Human diseases caused by mutations in extracellular matrix (ECM) genes are often associated with an increased risk of cataract. In other systems, expression of mutant proteins causes endoplasmic reticulum (ER) stress and activates the Unfolded Protein Response (UPR). UPR is initially cytoprotective and aims at restoring ER homeostasis by attenuating general translation and increasing ER folding capacity. However if the stress is acute or prolonged, UPR triggers cell death. Here we test the hypothesis that the presence of abnormal ECM in the lens results in cataract due to activation of the UPR.

Methods: : Transgenic mice were created harboring constructs consisting of the hybrid promoter ΔEN/αAcrystallin driving expression of either the mouse collagen α3(IV) or α4(IV) cDNA. Alterations in lens structure were measured by darkfield microscopy and conventional histology. The evaluation of the crystallins and molecular markers of UPR was tested by immunohistochemistry, rt-PCR and Western blotting. Apoptosis was assessed by active caspase-3 staining. Cell proliferation was detected by BrdU labeling.

Results: : In cataractous transgenic lenses expressing ectopic collagen α3(IV) or α4(IV), unassembled chains started accumulating in fiber cell cytoplasm around 11.5 dpc. Subsequently, transgenic lenses exhibited a large upregulation of BiP, an ER resident chaperone whose expression is a marker for UPR activation. The transcription factor Xbp1 is known to control a large group of UPR-responsive genes including BiP. In transgenic lenses we detected the ER-stress induced splicing of Xbp1 mRNA and the production of the Xbp1 protein. A major cytoprotective component of the UPR is the inhibition of protein translation through phosphorylation of eIF2α. We detected about 50% decrease in protein translation rate in the transgenic lenses which caused a general decrease in crystallin levels and followed by the failure of fiber cell elongation around 15.5 dpc. Activation of UPR signaling did not induce apoptosis in these transgenic lenses. Also, UPR did not affect cell proliferation.

Keywords: cataract • extracellular matrix • genetics 
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