title: Exclusion of the unfolded protein response in light-induced retinal degeneration in the canine T4R RHO model of autosomal dominant retinitis pigmentosa.
abstract: OBJECTIVE
  To examine the occurrence of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) following acute light damage in the naturally-occurring canine model of RHO-adRP (T4R RHO dog).
  
  
  METHODS
  The left eyes of T4R RHO dogs were briefly light-exposed and retinas collected 3, 6 and 24 hours later. The contra-lateral eyes were shielded and used as controls. To evaluate the time course of cell death, histology and TUNEL assays were performed. Electron microscopy was used to examine ultrastructural alterations in photoreceptors at 15 min, 1 hour, and 6 hours after light exposure. Gene expression of markers of ER stress and UPR were assessed by RT-PCR, qRT-PCR and western blot at the 6 hour time-point. Calpain and caspase-3 activation were assessed at 1, 3 and 6 hours after exposure.
  
  
  RESULTS
  A brief exposure to clinically-relevant levels of white light causes within minutes acute disruption of the rod outer segment disc membranes, followed by prominent ultrastructural alterations in the inner segments and the initiation of cell death by 6 hours. Activation of the PERK and IRE1 pathways, and downstream targets (BIP, CHOP) of the UPR was not observed. However increased transcription of caspase-12 and hsp70 occurred, as well as calpain activation, but not that of caspase-3.
  
  
  CONCLUSIONS
  The UPR is not activated in the early phase of light-induced photoreceptor cell death in the T4R RHO model. Instead, disruption in rods of disc and plasma membranes within minutes after light exposure followed by increase in calpain activity and caspase-12 expression suggests a different mechanism of degeneration.
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Stefania
authors.initials: S
authors.lastname: Marsili
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Sem
authors.initials: S
authors.lastname: Genini
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Raghavi
authors.initials: R
authors.lastname: Sudharsan
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Gingrich
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Beltran
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D004285:Dogs; D020287:In Situ Nick-End Labeling; D008027:Light / Q000009:adverse effects*; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000378:metabolism* / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*
chemical_list: D012243:Rhodopsin