We have updated our privacy policy. If you have any question, contact us at privacy@scicrunch.org. Dismiss and don't show again

Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.

Nature | Jul 29, 2010

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 RIS Download

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 | Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 | Male | MicroRNAs | Neurons | Parkinson Disease | Protein Binding | Protein Biosynthesis | Protein-Serine-Threonine Kinases | RNA, Messenger | RNA-Induced Silencing Complex | Trans-Activators | Up-Regulation

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

Associated grants

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

BioGRID (Data, Interactions)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.