title: Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.
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.
authors.affiliation: Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Vision Science Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Bhootada
authors.affiliation: Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Vision Science Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Pravallika
authors.initials: P
authors.lastname: Kotla
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Sergei
authors.initials: S
authors.lastname: Zolotukhin
authors.affiliation: Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Vision Science Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Center for Neurodegeneration and Experimental Therapy, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Oleg
authors.initials: O
authors.lastname: Gorbatyuk
authors.affiliation: Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bebok
authors.affiliation: Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.affiliation: Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Vision Science Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Gorbatyuk
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000378:metabolism*; D012243:Rhodopsin / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology
chemical_list: C081452:Atf4 protein, mouse; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D012243:Rhodopsin; D053148:Caspase 3; D053179:Caspase 7