July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
The functional nonequivalence of α-crystallins in the lens proteostasis network
Author Affiliations & Notes
  • Shu-Yu Wu
    Molecular Physiology and Biophysics, Vanderbilt University, Nashviile, Tennessee, United States
  • Hassane S Mchaourab
    Molecular Physiology and Biophysics, Vanderbilt University, Nashviile, Tennessee, United States
  • Footnotes
    Commercial Relationships   Shu-Yu Wu, None; Hassane Mchaourab, None
  • Footnotes
    Support  NIH Grant EY12018
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3487. doi:
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      Shu-Yu Wu, Hassane S Mchaourab; The functional nonequivalence of α-crystallins in the lens proteostasis network. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3487.

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

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Abstract

Purpose : Consistent with their known roles in maintaining the lens transparency, mutations in human αA- or αB-crystallin have been implicated in various inherited congenital cataracts. Our previous works demonstrated that loss of αA- or αB-crystallin will lead to a spectrum of defects in the zebrafish embryonic lens due to compromised proteostatic network. Given their similar functions as lens resident chaperones, we hypothesized that αA- and αB-crystallin may be interchangeable for lens defects. To test this hypothesis in vivo, we examined the modulating effects of αA- and αB-crystallin on the zebrafish embryonic lens defects by transgenic approaches.

Methods : Lens-specific transgenic lines expressing murine αA- and αB-crystallin (Tg[αA-WT] and Tg[αB-WT]) were generated by Tol2 transgenesis, and crossed into different zebrafish transgenic or mutant lines that exhibit lens defects. Lens defects in zebrafish larvae (4 dpf) were examined and compared between transgene carriers and non-transgenic siblings.

Results : First, we examined the modulating effects of αA- and αB-crystallin on the lens defects induced by lens expression of destabilized γD-crystallin, Tg[γD-I4F/V76D]. Compared to exogenous expression of rat αΑ-crystallin (Tg[αA-WT]), which showed no protective effects on lens defects induced by γD-crystallin I4F/V76D, we found that expression of mouse αB-crystallin (Tg[αB-WT]) was capable of providing alleviation for the lens defects in the Tg[γD-I4F/V76D] embryos. Moreover, we tested if Tg[αB-WT] could suppress the severe lens defects observed in the cloche mutant. In contrast to the robust partial rescue by expressing αA-crystallin transgene, we found no apparent suppression of the lens defect in cloche mutant carrying αB-crystallin transgene, compared to cloche mutant siblings. Finally, by comparing the rescuing efficiency of transgenic expression of each α-crystallin on the reciprocal mutants, we also found no evidence supporting the interchangeability between αA- and αB-crystallin, as neither could compensate the loss of their counterpart.

Conclusions : Even though the differential anti-apoptotic abilities of αA- and αB-crystallin have been shown in vitro, our in vivo study reaffirmed that αA-crystallin and αB-crystallin are not functionally exchangeable despite both being important constituents of the lens proteostatic network and their function as molecular chaperones.

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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