DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration

Paper of the Month: December, 2011

Nature. 2011 Mar 17;471(7338):325-30. Epub 2011 Feb 6. doi: doi:10.1038/nature09830.

Hiroki KanekoSami DridiValeria TaralloBradley D. GelfandBenjamin J. FowlerWon Gil ChoMark E. KleinmanSteven L. PonicsanWilliam W. HauswirthVince A. ChiodoKatalin KarikóJae Wook YooDong-ki LeeMajda HadziahmetovicYing SongSmita MisraGautam ChaudhuriFrank W. BuaasRobert E. BraunDavid R. HintonQing ZhangHans E. GrossniklausJan M. ProvisMichele C. MadiganAnn H. Milamet al.


Click here for Pubmed Abstract


Comments by Dr. Murray Gardner:

Age-related macular degeneration( MD ) is a leading cause of blindness for which there is no effective therapy. The pathogenesis involves extensive atrophy of the retinal pigment epithelium( RPE ). A fascinating paper in Nature identifies a novel pathogenic mechanism in which dysregulation of the RNAase DICER  allows  the accumulation of Alu transcripts in the RPE. Alu elements are a family of still active mobile DNA ( retrotransposons ) that are associated with insertional mutagenesis and disease in humans. They are especially active in the human brain where they may reshape the genetic circuity that underlies normal and abnormal neurobiological processes.

This paper shows that the microRNA processing enzyme DICER is reduced in the RPE of humans with MD and ablation of DICER induces RPE degeneration in mice. DICER knockdown also induces accumulation of Alu RNA in human and mouse RPE cells. Alu RNA is increased in the RPE of humans with MD and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice.  DICER depletion-induced RPE degeneration.  DICER degrades Alu RNA and the digested Alu transcripts can not induce RPE degeneration in mice. These findings indicate that Alu RNA can directly cause macular degeneration and DICER plays a protective role by degrading Alu RNA, thus identifying new targets for therapy.

I especially like this paper because my mother suffered from age-related macular degeneration and I spent a long time looking unsuccessfully for infectious  endogenous retroviruses in humans.  Retrotransposons  are certainly not viruses , although they may have given rise to them, but they replicate by a similar “cut and paste” mechanism that relies on the enzyme reverse transcriptase that was discovered in the exogenous RNA Tumor Viruses (oncoretroviruses) of chickens and mice,  discovered  many years ago,  an exciting era that Bob Cardiff and  I participated in.



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