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Bradley Gelfand, Mark Kleinman, Jayakrishna Ambati; Cytotoxic Alu RNA accumulation in the RPE mediated by iron overload. Invest. Ophthalmol. Vis. Sci. 2013;54(15):362.
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The loss of DICER1 activity, which occurs in macular RPE in geographic atrophy, leads to accumulation of cytotoxic Alu RNAs. A recent report identified free cytosolic iron as an endogenous inhibitor of DICER1 activity, through the sequestration of PCBP2, a novel cofactor for DICER1 activity. The association between iron overload and retinal degeneration, led us to speculate that excess iron accumulation in the RPE is responsible for impaired DICER1 activity, and thus promotes RPE degeneration in human geographic atrophy.
Iron overload was induced by pretreatment with ferric ammonium citrate. Intracellular iron chelation was acheived by pretreatment with Deferiprone. Synthetic Alu RNA labeled with biotin was generated by in vitro transcription.
Iron chelation prevented Alu RNA-mediated RPE degeneration. Iron pretreatment increased Alu RNA stability, whereas iron chelation promoted Alu RNA degradation. Mass spectroscopic analysis identified PCBP2 as a novel binding partner for Alu RNA. siRNA-mediated knockdown of PCBP2 prevented Alu RNA degradation. Finally, we detected physical interaction between Alu RNA and PCBP2, which was inhibited by iron pretreatment.
These findings suggest that iron homeostasis may be an important factor in regulating cellular Alu RNA levels, and advocate for further study in human retinal diseases associated with increased iron content including age-related macular degeneration .
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