Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression

Stephan Gehrke (), Yuzuru Imai, Nicholas Sokol and Bingwei Lu ()
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Stephan Gehrke: Stanford University School of Medicine
Yuzuru Imai: Institute of Development, Aging and Cancer, Tohoku University
Nicholas Sokol: Indiana University
Bingwei Lu: Stanford University School of Medicine

Nature, 2010, vol. 466, issue 7306, 637-641

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature09191

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