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Inactivation of the Akt survival pathway during photoreceptor apoptosis in the retinal degeneration mouse
Catherine Jomary1, Jason Cullen, Stephen E Jones
1Retinitis Pigmentosa Research Unit, The Rayne Institute, Wolfson Centre for Age-Related Diseases, School of Biomedical and Health Sciences, King's College London, St. Thomas' Hospital, London, United Kingdom. catherine.jomary@kcl.ac.uk
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 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.
Insights
Photoreceptor cell death in rd mice involves inactivation of the Akt survival pathway and activation of apoptotic pathways. This dysregulation contributes to retinal degeneration.
Area of Science:
- Retinal degeneration research
- Molecular mechanisms of cell death
- Neuroscience
Background:
- The Akt signaling pathway is crucial for cell survival.
- Loss of Akt signaling can trigger apoptosis.
- Photoreceptor cell death is a hallmark of retinal degeneration.
Purpose of the Study:
- To investigate the role of the Akt survival pathway in photoreceptor cell death.
- To examine Akt pathway regulation in the rd mouse model of retinal degeneration.
Main Methods:
- Quantitative Western blot and immunocytochemistry were used.
- Key Akt pathway components (Akt, BAD, FKHR, PTEN, etc.) were analyzed.
- Retinas from rd mice and controls were compared during degeneration.
Main Results:
- Dysregulation of the Akt survival pathway was observed.
- Deactivation of Akt and its target Forkhead (FKHR) occurred.
- Activation of the negative regulator PTEN was noted.
Conclusions:
- Photoreceptor cell death in rd mice results from Akt pathway inactivation.
- This inactivation combines with activation of major apoptotic pathways.
- Data support a model of combined survival and apoptotic pathway dysregulation.
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