Doonan Francesca, Cotter Thomas G
Tumour Biology Laboratory, Biochemistry Department, Bioscience Research Institute, University College Cork, Cork, Ireland.
Curr Neurovasc Res. 2004 Jan;1(1):41-53. doi: 10.2174/1567202043480215.
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.
许多遗传性和诱发性视网膜变性的特征是视力丧失，这与光感受器的死亡有关。遗传性视网膜疾病，包括色素性视网膜炎（RP），是发达国家失明的最大单一原因。RP的遗传学很复杂，除了每个基因中存在的众多突变（例如视紫红质有<100个）外，大约有48个基因与这种疾病的病理有关。试图克服每个个体突变带来了巨大挑战。然而，针对凋亡，这是光感受器细胞死亡的高度受控的最终共同途径，可能提供一种更实际的方法。在许多系统中，半胱天冬酶被认为是凋亡的主要执行者，然而现在很明显，其他蛋白酶如钙蛋白酶和组织蛋白酶也与凋亡有关。鉴于有报道表明该途径的关键成分在视网膜发育过程中被下调，将对关于半胱天冬酶在视网膜变性凋亡执行中的作用的相互矛盾的数据进行批判性讨论。这可能控制发育中的视网膜以及其他有丝分裂后细胞如神经元、心脏和骨骼肌成熟过程中对凋亡的易感性。线粒体通过其在能量产生、钙稳态和细胞死亡激活剂的区室化中的作用，作为凋亡内在途径的中心调节者。还将特别强调Bcl-2家族蛋白和钙内流调节因子的作用，研究控制这些凋亡蛋白从线粒体释放的潜力。
