Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression (original) (raw)

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• Published: 29 July 2010

Nature volume 466, pages 637–641 (2010)Cite this article

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Abstract

Gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2) cause familial as well as sporadic Parkinson’s disease characterized by age-dependent degeneration of dopaminergic neurons1,2. The molecular mechanism of LRRK2 action is not known. Here we show that LRRK2 interacts with the microRNA (miRNA) pathway to regulate protein synthesis. Drosophila e2f1 and dp messenger RNAs are translationally repressed by let-7 and miR-184*, respectively. Pathogenic LRRK2 antagonizes these miRNAs, leading to the overproduction of E2F1/DP, previously implicated in cell cycle and survival control3 and shown here to be critical for LRRK2 pathogenesis. Genetic deletion of let-7, antagomir-mediated blockage of let-7 and miR-184* action, transgenic expression of dp target protector, or replacement of endogenous dp with a dp transgene non-responsive to let-7 each had toxic effects similar to those of pathogenic LRRK2. Conversely, increasing the level of let-7 or miR-184* attenuated pathogenic LRRK2 effects. LRRK2 associated with Drosophila Argonaute-1 (dAgo1) or human Argonaute-2 (hAgo2) of the RNA-induced silencing complex (RISC). In aged fly brain, dAgo1 protein level was negatively regulated by LRRK2. Further, pathogenic LRRK2 promoted the association of phospho-4E-BP1 with hAgo2. Our results implicate deregulated synthesis of E2F1/DP caused by the miRNA pathway impairment as a key event in LRRK2 pathogenesis and suggest novel miRNA-based therapeutic strategies.

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Acknowledgements

We thank R. W. Carthew, B. Dickson, B. Edgar, D. St Johnston, N. Sonenberg, W. Smith, Z. Zhang, H. Siomi, B. Hay, S. Cohen, the Vienna Drosophila RNAi Center and the Bloomington Drosophila Stock Center for fly stocks and cell line, and Bestgene Inc. for help with making gDPwt and gDPmut transgenics; N. J. Dyson, R. P. Wharton, C. Zeng, G. Meister and Y. Liu for antibodies; T. Tuschl, P. A. Sharp and Y. Tomari for plasmids; P. Sarnow and R. Cevallos for advice on polysome preparation; S. Guo and A. Fire for reading the manuscript; W. Lee and G. Silverio for technical support; and members of the Lu laboratory for discussions. This work was supported by the National Institutes of Health (R01AR054926, R01MH080378 and R21NS056878), the McKnight, Beckman and Sloan Foundations (B.L.), and the Program for Young Researchers from Special Coordination Funds for Promoting Science and Technology commissioned by MEXT in Japan and an Asahi Glass Foundation Research Grant (Y.I).

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Authors and Affiliations

1. Department of Pathology, Stanford University School of Medicine, Stanford, 94305, California, USA
   Stephan Gehrke & Bingwei Lu
2. Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
   Yuzuru Imai
3. Department of Biology, Indiana University, Bloomington, 47405, Indiana, USA
   Nicholas Sokol

Authors

1. Stephan Gehrke
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2. Yuzuru Imai
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3. Nicholas Sokol
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4. Bingwei Lu
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Contributions

S.G. designed and performed the experiments and wrote the manuscript; Y.I. performed the experiments; N.S. provided key reagents and advice; B.L. designed the experiments, wrote the paper and provided funding.

Corresponding authors

Correspondence toStephan Gehrke or Bingwei Lu.

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The authors declare no competing financial interests.

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Gehrke, S., Imai, Y., Sokol, N. et al. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.Nature 466, 637–641 (2010). https://doi.org/10.1038/nature09191

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• Received: 11 December 2008
• Accepted: 20 May 2010
• Issue Date: 29 July 2010
• DOI: https://doi.org/10.1038/nature09191

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Editorial Summary

MicroRNAs in Parkinson's

Mutations in leucine-rich repeat kinase 2 (LRRK2) have been linked to both familial and sporadic Parkinson's disease, but the biochemical function of LRRK2 has remained elusive. Now that function has been discovered. Both Drosophila and human LRRK2 are shown to antagonize microRNA-mediated translational inhibition of E2F1 and DP transcription factors. LRRK2 interacts with the RNA-induced silencing complex component Argonaute to antagonize its suppressive effect on protein translation. In vivo genetic studies demonstrate a key role for E2F1/DP upregulation in mediating mutant LRRK2 pathogenesis. These findings point to a link between impaired microRNA-mediated silencing and deregulated expression of specific microRNA targets to Parkinson's disease pathogenesis, and suggest possible microRNA-based therapeutic approaches.