PMID- 20671708
OWN - NLM
STAT- MEDLINE
DCOM- 20100921
LR  - 20211203
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 466
IP  - 7306
DP  - 2010 Jul 29
TI  - Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.
PG  - 637-41
LID - 10.1038/nature09191 [doi]
AB  - 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.
FAU - Gehrke, Stephan
AU  - Gehrke S
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, 
      California 94305, USA. sgehrke@stanford.edu
FAU - Imai, Yuzuru
AU  - Imai Y
FAU - Sokol, Nicholas
AU  - Sokol N
FAU - Lu, Bingwei
AU  - Lu B
LA  - eng
GR  - R01AR054926/AR/NIAMS NIH HHS/United States
GR  - R21NS056878/NS/NINDS NIH HHS/United States
GR  - R01 MH080378/MH/NIMH NIH HHS/United States
GR  - R21 NS056878-01A1/NS/NINDS NIH HHS/United States
GR  - R01 MH080378-01A2/MH/NIMH NIH HHS/United States
GR  - R01MH080378/MH/NIMH NIH HHS/United States
GR  - R01 AR054926-01A2/AR/NIAMS NIH HHS/United States
GR  - R01 AR054926/AR/NIAMS NIH HHS/United States
GR  - R21 NS056878/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (AGO1 protein, Drosophila)
RN  - 0 (AGO2 protein, human)
RN  - 0 (Argonaute Proteins)
RN  - 0 (Dp transcription factor, Drosophila)
RN  - 0 (Drosophila Proteins)
RN  - 0 (E2F1 Transcription Factor)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Let-7 microRNA, Drosophila)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn184 microRNA, Drosophila)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Induced Silencing Complex)
RN  - 0 (Trans-Activators)
RN  - EC 2.7.11.1 (LRRK protein, Drosophila)
RN  - EC 2.7.11.1 (LRRK2 protein, human)
RN  - EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
CIN - Nat Rev Neurosci. 2010 Sep;11(9):609. PMID: 20803789
MH  - Animals
MH  - Argonaute Proteins
MH  - Cell Line
MH  - Dopamine/metabolism
MH  - *Down-Regulation
MH  - Drosophila Proteins/biosynthesis/genetics/metabolism
MH  - Drosophila melanogaster
MH  - E2F1 Transcription Factor/biosynthesis/genetics/metabolism
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - Eukaryotic Initiation Factors/biosynthesis/metabolism
MH  - Female
MH  - Humans
MH  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
MH  - Male
MH  - MicroRNAs/antagonists & inhibitors/*genetics/*metabolism
MH  - Neurons/cytology/metabolism
MH  - Parkinson Disease/etiology/genetics/metabolism
MH  - Protein Binding
MH  - *Protein Biosynthesis
MH  - Protein Serine-Threonine Kinases/*genetics/*metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - RNA-Induced Silencing Complex/antagonists & inhibitors/chemistry/metabolism
MH  - Trans-Activators/biosynthesis/genetics/metabolism
MH  - Up-Regulation
PMC - PMC3049892
MID - NIHMS269498
EDAT- 2010/07/31 06:00
MHDA- 2010/09/23 06:00
PMCR- 2011/03/08
CRDT- 2010/07/31 06:00
PHST- 2008/12/11 00:00 [received]
PHST- 2010/05/20 00:00 [accepted]
PHST- 2010/07/31 06:00 [entrez]
PHST- 2010/07/31 06:00 [pubmed]
PHST- 2010/09/23 06:00 [medline]
PHST- 2011/03/08 00:00 [pmc-release]
AID - nature09191 [pii]
AID - 10.1038/nature09191 [doi]
PST - ppublish
SO  - Nature. 2010 Jul 29;466(7306):637-41. doi: 10.1038/nature09191.