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Glutamate and Hypoxia as a Stress Model for the Isolated Perfused Vertebrate Retina
Published on: March 22, 2015
FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina
Mercy Pawar1, Boris Busov1, Aaruran Chandrasekhar1
1Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA.
Abstract:
We report the neuroprotective role of FAS apoptotic inhibitory molecule 2 (FAIM2), an inhibitor of the FAS signaling pathway, during stress-induced photoreceptor apoptosis. Retinal detachment resulted in increased FAIM2 levels in photoreceptors with higher amounts detected at the tips of outer segments. Activation of FAS death receptor via FAS-ligand led to JNK-mediated FAIM2 phosphorylation, decreased proteasome-mediated degradation and increased association with the FAS receptor. Photoreceptor apoptosis was accelerated in Faim2 knockout mice following experimental retinal detachment. We show that FAIM2 is primarily involved in reducing stress-induced photoreceptor cell death but this effect was transient. FAIM2 was found to interact with both p53 and HSP90 following the activation of the FAS death pathway and FAIM2/HSP90 interaction was dependent on the phosphorylation of FAIM2. Lack of FAIM2 led to increased expression of proadeath genes Fas and Ripk1 in the retina under physiologic conditions. These results demonstrate that FAIM2 is an intrinsic neuroprotective factor activated by stress in photoreceptors and delays FAS-mediated photoreceptor apoptosis. Modulation of this pathway to increase FAIM2 expression may be a potential therapeutic option to prevent photoreceptor death.
Insights
FAS apoptotic inhibitory molecule 2 (FAIM2) protects photoreceptors from stress-induced death by inhibiting the FAS pathway. FAIM2 delays photoreceptor apoptosis, offering a potential therapeutic target for retinal diseases.
Area of Science:
- Ophthalmology
- Neuroscience
- Cell Biology
Background:
- Photoreceptor apoptosis contributes to vision loss in retinal diseases.
- The FAS signaling pathway is a key mediator of programmed cell death.
- FAIM2 is an inhibitor of the FAS pathway with potential neuroprotective roles.
Purpose of the Study:
- To investigate the role of FAIM2 in stress-induced photoreceptor apoptosis.
- To elucidate the molecular mechanisms underlying FAIM2's neuroprotective function.
- To assess the therapeutic potential of modulating FAIM2 in retinal injury.
Main Methods:
- Utilized a mouse model of experimental retinal detachment.
- Analyzed FAIM2 expression and localization in photoreceptors.
- Investigated FAIM2 phosphorylation, degradation, and interaction with FAS receptor and associated proteins (p53, HSP90) using Western blotting and co-immunoprecipitation.
- Assessed photoreceptor apoptosis in wild-type and Faim2 knockout mice.
Main Results:
- Retinal detachment increased FAIM2 levels in photoreceptors, particularly at outer segment tips.
- JNK-mediated FAIM2 phosphorylation reduced its degradation and increased its association with the FAS receptor.
- FAIM2 deficiency accelerated photoreceptor apoptosis following retinal detachment.
- FAIM2 interacted with p53 and HSP90, with HSP90 interaction dependent on FAIM2 phosphorylation.
- Lack of FAIM2 increased pro-death gene expression (Fas, Ripk1) under normal conditions.
Conclusions:
- FAIM2 is an intrinsic neuroprotective factor activated by stress in photoreceptors.
- FAIM2 delays FAS-mediated photoreceptor apoptosis, though this effect is transient.
- Modulating FAIM2 levels may offer a therapeutic strategy to prevent photoreceptor death in retinal diseases.
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