加齢黄斑変性症とDicerと反復配列Alu：natureに続いて今回はCell

去年印象に残る報告の一つが加齢黄斑変性症の原因がDicerであり反復配列Aluの細胞内蓄積（細胞毒）であるというnature論文だった。続報なのだろう。最新のセルにまた一報載っている。反復配列オタクの小生としては見逃せない報告だ。

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最近気になる論文から・・・３報

Nature　471,325–330　06 February 2011
DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration

加齢黄斑変性症の原因の一つがDICER1(RNA のプロセッシングユニット）によることも面白ければ、こともあろうに反復配列「Alu」が蓄積することが細胞毒になるというという事象も初めて聞く話で面白かった。

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Cell, 26 April 2012

DICER1 Loss and Alu RNA Induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88

Authors

Valeria Tarallo, Yoshio Hirano, Bradley D. Gelfand, Sami Dridi, Nagaraj Kerur, Younghee Kim, Won Gil Cho, Hiroki Kaneko, Benjamin J. Fowler, Sasha Bogdanovich, Romulo J.C. Albuquerque, William W. Hauswirth, Vince A. Chiodo, Jennifer F. Kugel, James A. Goodrich, Steven L. Ponicsan, Gautam Chaudhuri, Michael P. Murphy, Joshua L. Dunaief, Balamurali K. Ambati, Yuichiro Ogura, Jae Wook Yoo, Dong-ki Lee, Patrick Provost, David R. Hinton, Gabriel Núñez, Judit Z. Baffi, Mark E. Kleinman, Jayakrishna Ambati

• Highlights
• Alu RNA accumulation due to DICER1 deficiency activates NLRP3 inflammasome in RPE
• Pharmacological inhibition of the inflammasome, MyD88, or IL18 prevents degeneration
• Alu RNA induced RPE degeneration via mitochondrial ROS production, IL18, and MyD88
• RPE in human geographic atrophy eyes display evidence of NLRP3 and MyD88 activation

• Summary

• Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.