Identification of a Common Non-Apoptotic Cell Death Mechanism in Hereditary Retinal Degeneration
Figure 6
Classical apoptosis, such as it occurs in S334ter transgenic photoreceptors, involves a mutation-induced up-regulation and translocation of BAX protein to form the mitochondrial permeability transition pore (MPTP). This leads to leakage of cytochrome c from the mitochondria to the cytoplasm, where it combines with apoptotic protease activating factor (APAF) and caspase-9 to form the apoptosome, which in turn activates down-stream executioner caspases, including caspase-3. In 9/10 RD animal models investigated here, photoreceptor death followed a different route: mutation-induced up-regulation of cGMP on the one hand causes activation of the CNG channel, leading to Ca2+ influx and calpain activation. On the other hand cGMP-dependent activation of protein kinase G (PKG) is associated with histone deacetylase (HDAC) and poly-ADP-ribose-polymerase (PARP) activation. Importantly, this alternative, non-apoptotic cell death mechanism offers a number of novel targets for neuroprotection of photoreceptors.