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Wei Du, Xingwang Xie, Xin Tang, Xiaoxin Li; Rhodopsin P23H mutation promote photoreceptor degeneration through GSDMD mediated pyroptosis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4545. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The P23H mutation in rhodopsin is one of the most frequent mutations in retinitis pigmentosa (RP), which could induce the degeneration of photoreceptor cells. Pyroptosis is an inflammatory form of cell death that has been shown to involved in several degenerative diseases. But, the exact role of pyroptosis in the progression of RP was not elucidated.
Homozygous RhoP23H mutation mice from Jackson Labs were used for this study. Retina from these mice was subjected to H&E staining, electron microscopy and electroretinography (ERG) analysis to measure the morphology and function of photoreceptor cell layer. Western blot was used to detect the protein level of GSDMD in retina. Moreover, GSDMD in photoreceptor cells was knocking down in vivo by subretinal injection of AAV particles expressing GSDMD specific sgRNA and saCas9 under the control of mice rhodopsin promoter.
We found that both full length and N terminal fragment (active form) of GSDMD protein was dramatically upregulated in the retina of homozygous RhoP23H mutation mice at postnatal day 4 to day 15. We further proved that knocking down of GSDMD specifically in rod cell with CRISPR/Cas9 could effectively prevent the degeneration of photoreceptor cell and preserve its electrical response function in RhoP23H mutation mice.
In summary, GSDMD mediated pyroptosis play a major role in rhodopsin P23H mutation induced photoreceptor degeneration and could be a promising treatment target in RP.
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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