title: Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration.
abstract: Inherited retinal disorders (IRDs) result in severe visual impairments in children and adults. A challenge in the field of retinal degenerations is identifying mechanisms of photoreceptor cell death related to specific genetic mutations. Mutations in the gene TULP1 have been associated with two forms of IRDs, early-onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). TULP1 is a cytoplasmic, membrane-associated protein shown to be involved in transportation of newly synthesized proteins destined for the outer segment compartment of photoreceptor cells; however, how mutant TULP1 causes cell death is not understood. In this study, we provide evidence that common missense mutations in TULP1 express as misfolded protein products that accumulate within the endoplasmic reticulum (ER) causing prolonged ER stress. In an effort to maintain protein homeostasis, photoreceptor cells then activate the unfolded protein response (UPR) complex. Our results indicate that the two major apoptotic arms of the UPR pathway, PERK and IRE1, are activated. Additionally, we show that retinas expressing mutant TULP1 significantly upregulate the expression of CHOP, a UPR signaling protein promoting apoptosis, and undergo photoreceptor cell death. Our study demonstrates that the ER-UPR, a known mechanism of apoptosis secondary to an overwhelming accumulation of misfolded protein, is involved in photoreceptor degeneration caused by missense mutations in TULP1. These observations suggest that modulating the UPR pathways might be a strategy for therapeutic intervention.
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States of America.
authors.forename: Glenn P
authors.initials: GP
authors.lastname: Lobo
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States of America.
authors.forename: Adrian
authors.initials: A
authors.lastname: Au
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, 44106, United States of America.|Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, 44106, United States of America.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Kiser
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States of America.|Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, 44195, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Hagstrom
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018274:Electroporation; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005136:Eye Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D020125:Mutation, Missense / Q000502:physiology; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000209:etiology / Q000235:genetics*; D013312:Stress, Physiological / Q000502:physiology; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology
chemical_list: D005136:Eye Proteins; C105443:TULP1 protein, human