July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
HIGH EXPRESSION OF MONOMERIC ARRESTIN-1 CAUSES RETINAL DEGENERATION
Author Affiliations & Notes
  • Srimal Aminda Samaranayake
    Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • Sergey A Vishnivetskiy
    Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • Kimberly C Thibeault
    Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • Eugenia Gurevich
    Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • Vsevolod V Gurevich
    Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Srimal Samaranayake, None; Sergey Vishnivetskiy, None; Kimberly Thibeault, None; Eugenia Gurevich, None; Vsevolod Gurevich, None
  • Footnotes
    Support  RO1 and EY011500
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3063. doi:
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      Srimal Aminda Samaranayake, Sergey A Vishnivetskiy, Kimberly C Thibeault, Eugenia Gurevich, Vsevolod V Gurevich; HIGH EXPRESSION OF MONOMERIC ARRESTIN-1 CAUSES RETINAL DEGENERATION. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3063.

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

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Abstract

Purpose : To test the biological role of arrestin-1 self-association.

Methods : Several transgenic mouse lines that express arrestin-1 mutant deficient in self-association were created. The transgene expression ranged from 77% to 292%, relative to wild type (WT) level. Retinal morphology and electroretinograms (ERG) were characterized.

Results : We previously found that high expression of arrestin-1-3A mutant induces rapid degeneration of rod photoreceptors. In contrast, high expression of WT arrestin-1 is not harmful and co-expression of WT arrestin-1 protects the rods against arrestin-1-3A toxicity. Arrestin-1-3A differed from WT in many functional characteristics in addition to its self-association deficiency. To determine the role of arrestin-1 self-association per se, we created transgenic lines expressing WT arrestin-1 that carried only mutations that prevented self-association. The moderate expression transgenic lines M10 (77%) and M4 (111%) showed normal retinal morphology up to one year of age and WT-like recovery kinetics in ERG. In contrast, high expressors M9 (271%) and M5 (292%) demonstrated age-dependent retinal degeneration: thinning of the outer nuclear layer (ONL) and shortening of rod outer segments. Furthermore, M5 and M9 lines showed attenuated ERG a-wave and slower recovery kinetics.

Conclusions : Collectively, these observations reveal the toxicity of highly expressed monomeric arrestin-1, suggesting that arrestin-1 oligomerizes to suppress cytotoxicity of the monomer, thereby preserving photoreceptor health.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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