RESUMEN
Photoreceptors are specialized sensory neurons essential for light detection in the human eye. Photoreceptor cell dysfunction and death cause vision loss in many eye diseases such as retinitis pigmentosa and achromatopsia. Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling have been implicated in the development and pathology of heritable forms of retinitis pigmentosa and achromatopsia. We review the role of ER stress and UPR in retinitis pigmentosa arising from misfolded rhodopsins (RHO) and in achromatopsia arising from genetic mutations in Activating Transcription Factor 6 (ATF6). This article is part of a Special Issue entitled SI:ER stress.
Asunto(s)
Estrés del Retículo Endoplásmico/fisiología , Células Fotorreceptoras de Vertebrados/patología , Células Fotorreceptoras de Vertebrados/fisiología , Enfermedades de la Retina/patología , Factor de Transcripción Activador 6/genética , Estrés del Retículo Endoplásmico/genética , Humanos , Mutación/genética , Enfermedades de la Retina/genética , Enfermedades de la Retina/fisiopatología , Respuesta de Proteína Desplegada/genética , Respuesta de Proteína Desplegada/fisiologíaRESUMEN
Endogenous murine amyloid-ß peptide (Aß) is expressed in most Aß precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to ß-amyloidosis remains unclear. We demonstrate â¼ 35% increased cerebral Aß load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster Aß-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine Aß, and immunoelectron microscopy revealed a tight association of murine Aß with human Aß fibrils. Deposition of murine Aß was considerably less efficient compared with the deposition of human Aß indicating a lower amyloidogenic potential of murine Aß in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human Aß and deposits of mixed human-murine Aß. Our data demonstrate a differential effect of murine Aß on human Aß deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse Aß may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.
