RRC ID 36837
著者 Bhootada Y, Kotla P, Zolotukhin S, Gorbatyuk O, Bebok Z, Athar M, Gorbatyuk M.
タイトル Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.
ジャーナル PLoS One
Abstract T17M rhodopsin expression in rod photoreceptors leads to severe retinal degeneration and is associated with the activation of ER stress related Unfolded Protein Response (UPR) signaling. Here, we show a novel role of a UPR transcription factor, ATF4, in photoreceptor cellular pathology. We demonstrated a pro-death role for ATF4 overexpression during autosomal dominant retinitis pigmentosa (ADRP). Based on our results in ATF4 knockout mice and adeno-associated viral (AAV) delivery of ATF4 to the retina, we validated a novel therapeutic approach targeting ATF4 over the course of retinal degeneration. In T17M rhodopsin retinas, we observed ATF4 overexpression concomitantly with reduction of p62 and elevation of p53 levels. These molecular alterations, together with increased CHOP and caspase-3/7 activity, possibly contributed to the mechanism of photoreceptor cell loss. Conversely, ATF4 knockdown retarded retinal degeneration in 1-month-old T17M Rhodopsin mice and promoted photoreceptor survival, as measured by scotopic and photopic ERGs and photoreceptor nuclei row counts. Similarly, ATF4 knockdown also markedly delayed retinal degeneration in 3-month-old ADRP animals. This delay was accompanied by a dramatic decrease in UPR signaling, the launching of anti-oxidant defense, initiation of autophagy, and improvement of rhodopsin biosynthesis which together perhaps combat the cellular stress associated with T17M rhodopsin. Our data indicate that augmented ATF4 signals during retinal degeneration plays a cytotoxic role by triggering photoreceptor cell death. Future ADRP therapy regulating ATF4 expression can be developed to treat retinal degenerative disorders associated with activated UPR.
巻・号 11(5)
ページ e0154779
公開日 2016-1-1
DOI 10.1371/journal.pone.0154779
PII PONE-D-16-00316
PMID 27144303
PMC PMC4856272
MeSH Activating Transcription Factor 4 / metabolism* Animals Autophagy / physiology* Caspase 3 / metabolism Caspase 7 / metabolism Disease Models, Animal Endoplasmic Reticulum / metabolism* Mice Mice, Inbred C57BL Mice, Knockout Retina / metabolism Retinal Degeneration / metabolism* Retinal Rod Photoreceptor Cells / metabolism* Retinitis Pigmentosa / metabolism* Rhodopsin / metabolism Stress, Physiological / physiology* Transcription Factors / metabolism Unfolded Protein Response / physiology
IF 2.74
引用数 16
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
実験動物マウス RBRC01099