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B. Rohrer, A. Sharma, H.R. Lohr, K. Kunchithapautham; Multiple, Parallel Cellular Suicide Mechanisms Participate in Photoreceptor Cell Death . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4745.
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Photoreceptor degeneration in human photoreceptor dystrophies and in the relevant animal models has been thought to be executed by one common mechanism – caspase–mediated apoptosis. However, recent experiments have challenged this concept. Previously, analyzing gene expression in the rd/rd mouse retina, we have suggested that the gene defect triggers caspase–dependent and caspase–independent cell death mechanisms such as the activation of cysteine–proteases, lysosomal proteases, autophagy and complement–mediated lysis. Here we asked two questions; (1) whether a temporal analysis of these different mechanisms during the course of degeneration would enable us to establish a causal relationship between these events; and (2), whether degeneration in different models of rod dystrophies occurs by activating the same mechanisms.
Three models were chosen: the rd/rd (calcium toxicity); the rds/rds mouse (structural defect); and light–damage (LD; oxidative stress). Marker genes were selected for the identified processes. The expression of these genes in the outer nuclear layer was verified by PCR–analysis on laser capture microdissection samples. A temporal relationship between the processes was established at the mRNA level, using quantitative RT–PCR. The time course of gene expression was compared to that of rod cell loss and apoptosis (TUNEL). Apoptosis and autophagy was verified using enzymatic assays.
The time course of apoptosis and TUNEL labeling coincide in all three models. Complement–activated lysis was found to either parallel (rd/rd and rds/rds) or precede (LD) the development of TUNEL–positive cells. Autophagy was determined to parallel (rd/rd and LD) or lag (rds/rds) behind the development of TUNEL–positive cells. In all three models, glucose metabolism was increased significantly prior to the onset of cell death, but then dropped in parallel with the loss of cells.
These results provide evidence that irrespective of whether photoreceptor degeneration is triggered by gene defects or environmental stress, multiple pro–apoptotic mechanisms are triggered leading to the degeneration of the photoreceptor cells. The temporal pattern of the different pathways suggests that the non–caspase–dependent mechanisms may actively participate in the demise of the photoreceptors, rather than represent a passive response of the retina to the presence of dying cells. Thus, unless the common upstream initiator for a given photoreceptor dystrophy is found, multiple rescue paradigms need to be used to target all active pathways.
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