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Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.

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 neurons. 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 control 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.

Pubmed ID: 20671708


  • Gehrke S
  • Imai Y
  • Sokol N
  • Lu B



Publication Data

July 29, 2010

Associated Grants

  • Agency: NIAMS NIH HHS, Id: R01 AR054926
  • Agency: NIAMS NIH HHS, Id: R01 AR054926-01A2
  • Agency: NIMH NIH HHS, Id: R01 MH080378
  • Agency: NIMH NIH HHS, Id: R01 MH080378-01A2
  • Agency: NIAMS NIH HHS, Id: R01AR054926
  • Agency: NIMH NIH HHS, Id: R01MH080378
  • Agency: NINDS NIH HHS, Id: R21 NS056878
  • Agency: NINDS NIH HHS, Id: R21 NS056878-01A1
  • Agency: NINDS NIH HHS, Id: R21NS056878

Mesh Terms

  • Animals
  • Argonaute Proteins
  • Cell Line
  • Dopamine
  • Down-Regulation
  • Drosophila Proteins
  • Drosophila melanogaster
  • E2F1 Transcription Factor
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factors
  • Female
  • Humans
  • Male
  • MicroRNAs
  • Neurons
  • Parkinson Disease
  • Protein Binding
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger
  • RNA-Induced Silencing Complex
  • Trans-Activators
  • Up-Regulation