Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78

摘要: The P23H mutation within the rhodopsin gene (RHO) causes misfolding, endoplasmic reticulum (ER) stress, and activates unfolded protein response (UPR), leading to rod photoreceptor degeneration autosomal dominant retinitis pigmentosa (ADRP). Grp78/BiP is an ER-localized chaperone that induced by UPR signaling in ER stress. We have previously demonstrated BiP mRNA levels are selectively reduced animal models of ADRP arising from expression at ages precede degeneration. now overexpressed test hypothesis this promotes trafficking cell membrane, reprograms favoring survival photoreceptors, blocks apoptosis, and, ultimately, preserves vision rats. In culture, increasing had no impact on localization rhodopsin. However, overexpression alleviated stress reducing cleaved pATF6 protein, phosphorylated eIF2α proapoptotic CHOP. rats, ATF6, pEIF2α, CHOP, caspase-7 were much higher than those wild-type Subretinal delivery AAV5 expressing transgenic rats led reduction CHOP apoptosis a sustained increase electroretinogram amplitudes. detected complexes between BiP, caspase-12, BH3-only BiK may contribute antiapoptotic activity BiP. Thus, preservation function resulting elevated due suppression rather promotion folding.