Apoptosis: a potential therapeutic target for retinal degenerations

Many retinal degenerations both inherited and induced are characterized by a loss of vision that is associated with death of photoreceptors. Inherited retinal diseases, which include Retinitis Pigmentosa (RP), form the largest single cause of blindness in the developed world. The genetics of RP is complex and approximately 48 genes have been implicated in the pathology of this disorder, in addition to the numerous mutations that exist within each gene (e.g. rhodopsin has <100). An attempt to overcome each individual mutation provides an overwhelming challenge. However targeting apoptosis, which represents a highly controlled, final common pathway to photoreceptor cell death, may provide a more practical approach. Caspases have been considered the primary executioners of apoptosis in many systems, however it is now apparent that other proteases such as calpains and cathepsins are affiliated with apoptosis. Conflicting data regarding the role of caspases in the execution of apoptosis in retinal degenerations will be critically discussed in light of reports demonstrating that key components of this pathway are downregulated during retinal development. This may control susceptibility to apoptosis in the developing retina and indeed during the maturation of other post-mitotic cells such as neurons and heart and skeletal muscle. Mitochondria function as central regulators of the intrinsic pathway of apoptosis through their role in energy production, calcium homeostasis and compartmentalization of cell death activators. The potential to control release of these apoptogenic proteins from mitochondria will also be examined with particular emphasis on the role of Bcl-2 family proteins and the regulators of calcium influx.