Reference Report

Reference
Citation	Gehrke, S., Imai, Y., Sokol, N., Lu, B. (2010). Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466(7306): 637--641. (Export to RIS)
FlyBase ID	FBrf0211387
Publication Type	Research paper
PubMed ID	20671708
PubMed 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 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.
DOI	10.1038/nature09191
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Language of Publication	English
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Publication Type	Journal
Abbreviation	Nature
Title	Nature
Publication Year	1869-
ISBN/ISSN	0028-0836
Data from Reference
Aberrations (3)
	Df(2L)let-7-C^GKI Df(2L)let-7-C^KO1 Df(2R)BSC272
Alleles (39)
	AGO1^k08121 AGO2⁴¹⁴ Avic\GFP^{EGFP.let-7-3'UTR.Scer\UAS} Avic\GFP^Scer\UAS.cUa ban^{D.Scer\UAS.T:Avic\GFP-EGFP} Dcr-1^Q1147X Dcr-1^Scer\UAS.cDa Dcr-1^VDRC.cUa Dp^49Fk-1 Dp^+tgDPwt Dp^gDPmut Dp^Scer\UAS.cGa Dp^{TP.let-7.Scer\UAS} E2f⁰⁷¹⁷² E2f^Scer\UAS.cNa eIF-4E^VDRC.cUa Hsap\LRRK2^{G2019S.Scer\UAS} Hsap\LRRK2^{Scer\UAS.T:Zzzz\FLAG} let-7^+tSa let-7^Scer\UAS.cGa let-7^Δ.cSa lkb1^4A4-2 Lrrk^3KD.Scer\UAS Lrrk^{dsRNA.Scer\UAS.cIa} Lrrk^{I1915T.Scer\UAS} Lrrk^{R1069G.Scer\UAS} Lrrk^Scer\UAS.cIa Lrrk^unspecified mir-14^GMR.PX mir-184^Scer\UAS.cGa Rbf^Scer\UAS.cDa Scer\GAL4^da.G32 Scer\GAL4^GMR.PF Scer\GAL4^let-7-C Scer\GAL4^ple.PF Thor^LL.Scer\UAS Thor^Scer\UAS.cMa Thor^TA.Scer\UAS Thor^TE.Scer\UAS
Constructs (31)
	P{GAL4-da.G32} P{GAL4-ninaE.GMR} P{gDPmut} P{gDPwt} P{GMR-mir-14.X} P{ple-GAL4.F} P{UAS-D} P{UAS-Dcr-1.D} P{UAS-Dp.TP.let-7} P{UAS-Dp.TP.wt} P{UAS-E2f.N} P{UAS-EGFP.let-7-3'UTR} P{UAS-GFP.U} P{UAS-hLRRK2.G2019S} P{UAS-let-7.pre} P{UAS-LRRK2.FLAG} P{UAS-Lrrk.3KD} P{UAS-Lrrk.I1915T} P{UAS-Lrrk.I} P{UAS-Lrrk.R1069G} P{UAS-Lrrk.RNAi} P{UAS-mir-184.pre} P{UAS-Rbf.D} P{UAS-Thor.LL} P{UAS-Thor.TA} P{UAS-Thor.TE} P{UAS-Thor.wt} P{VDRC.Dcr-1.U} P{VDRC.eIF-4E.U} P{W8,let-7-C} P{W8,let-7-C^Δlet-7}
Genes (18)
	AGO1 AGO2 Avic\GFP ban Dcr-1 Dp E2f eIF-4E Hsap\LRRK2 let-7 lkb1 Lrrk mir-14 mir-184 ple Rbf Scer\GAL4 Thor
Insertions (2)
	P{lacW}AGO1^k08121 P{PZ}E2f⁰⁷¹⁷²
Natural transposons (1)
	P-element