Inactivation of the Akt survival pathway during photoreceptor apoptosis in the retinal degeneration mouse

PURPOSE. Previous work has indicated that the serine-threonine protein kinase Akt is a general mediator of cellular survival signals and that loss of Akt-mediated signaling can lead to the activation of apoptosis. This study was conducted to establish whether regulation of the Akt survival pathway mechanisms is implicated in the induction of apoptosis during photoreceptor cell death in the rd mouse model of retinal degeneration. METHODS. Quantitative Western blot analysis and immunocytochemistry were Used to examine the activation status and localization of key components of the Akt signaling cascade (Akt, BAD, Forkhead [FKHR], HSP27, mitogen-activated protein (MAP) kinase kinase-3 and -6 (MKK3/6), the tumor-suppressor phosphatase PTEN, and the cytoplasmic protein-tyrosine kinase cSrc-p60), in the retina of the rd mouse in comparison with the control. The time points examined spanned the period of photoreceptor degeneration. RESULTS. In the period up to the peak of photoreceptor apoptosis at postnatal day 15, dysregulation of the survival pathway was identified at several levels, including deactivation of both Akt itself and its downstream transcription factor target Forkhead (FKHR) and activation of the Upstream negative regulator PTEN. CONCLUSIONS. Taken in conjunction with previous studies, the data support a,I model in which photoreceptor cell death in the rd mouse is the result of combined inactivation of the Akt Survival pathway and the activation of the two major apoptotic pathways.