Gehrke, S, Imai, Y, Sokol, N & Lu, B Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466, 637-641

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature (Impact Factor: 41.46). 07/2010; 466(7306):637-41. DOI: 10.1038/nature09191
Source: PubMed


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.

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    • "Several studies have indicated associations of miRNAs with some aspects of PD pathology (summarized in (Heman-Ackah et al., 2013;Ma et al., 2013;Wong and Nass, 2012)). " PD-specific " miRNA/target associations of interest have been miR-7, miR-153, and miR-34b/c with α-Synuclein, (Doxakis, 2010;Junn et al., 2009;Kabaria et al., 2015), miR-433 with FGF20 (Wang et al., 2008), miR-133b with PITX3 (Kim et al., 2007), let-7a-5p, miR-184-5p, and miR-205 with LRRK2 (Cho et al., 2013;Gehrke et al., 2010), miR-132 with NURR1 (Yang et al., 2012) or AChE (Shaked et al., 2009), and miR-34b/c indirectly with PARKIN and DJ1 (Minones-Moyano et al., 2011), and decreased expression of miR-133b and miR-34b/c, or miR-205 was identified in dissected human postmortem midbrain, or cortical tissue from sporadic PD patients, respectively . Except for miR-132 and miR-184, which were upregulated (Log2 FC 0.75; p ¼ 0.05, and Log2 FC 2.05; p ¼0.89, respectively), and miR-433, which was slightly, but not significantly downregulated (Log2 FC -0.09; p ¼ 0.4) in PD, our results did not provide strong support for a role of most of these miRNAs in DA neurons or PD: MiR-133b, miR-34b/c, miR-153, and miR-205 were expressed below detection threshold and miR-7 was not present on the TaqMan s Human MicroRNA A Array v2.0. "
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    ABSTRACT: The degeneration of substantia nigra (SN) dopamine (DA) neurons in sporadic Parkinson's disease (PD) is characterized by disturbed gene expression networks. Micro(mi)RNAs are post-transcriptional regulators of gene expression and we recently provided evidence that these molecules may play a functional role in the pathogenesis of PD. Here, we document a comprehensive analysis of miRNAs in SN DA neurons and PD, including sex differences. Our data show that miRNAs are dysregulated in disease-affected neurons and differentially expressed between male and female samples with a trend of more up-regulated miRNAs in males and more down-regulated miRNAs in females. Unbiased Ingenuity Pathway Analysis (IPA) revealed a network of miRNA/target-gene associations that is consistent with dysfunctional gene and signaling pathways in PD pathology. Our study provides evidence for a general association of miRNAs with the cellular function and identity of SN DA neurons, and with deregulated gene expression networks and signaling pathways related to PD pathogenesis that may be sex-specific. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jun 2015 · Brain research
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    • "Studies have suggested multiple mechanisms underlying the LRRK2 pathology (Greggio and Cookson 2009, Gehrke et al. 2010). In order to understand these mechanisms several animal models with wild type and mutant forms of human LRRK2 have been generated in nematodes (Saha et al. 2009, Hsu et al. 2010), flies (Liu et al. 2008) and rodents (Tong et al. 2009) and it was found that LRRK2 interacts with components involved in the autophagy lysosomal pathway (Tong et al. 2009) or protein quality control (Ng et al. 2009), modulate oxidative stress (Ng et al. 2009, Saha et al. 2009), regulate protein synthesis (Kanao et al. 2010), and mediate the microRNA pathway (Gehrke et al. 2010). Interesting reports have been achieved from the nematode, C.elegans demonstrating that expression of wild-type LRRK2 protects dopaminergic neurons against neurotoxcity induced by either 6-OHDA or human α-synuclein (Yuan et al. 2011). "
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    ABSTRACT: Parkinson’s disease is the second most common neurodegenerative disease which affects almost 1% of the population above the age of 60. It is is characterized by loss of dopaminergic neurons in the striatum and substantia nigra, coupled with the formation of intracellular Lewy bodies in degenerating neurons. Recent evidence suggests endoplasmic reticulum stress as a common and prominent occurrence in the progression of Parkinson’s disease pathogenesis in the affected human brain. One of the cellular defense mechanism to combat endoplasmic reticulum stress due to excessive protein accumulation is through activation of the unfolded protein response pathway. In this review we focus on the impact and role of this unfolded protein response as a causative factor of Parkinson’s disease leading to neurodegeneration.
    Full-text · Article · Apr 2015 · Acta neurobiologiae experimentalis
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    • "Fly LRRK binds to Argonaute-1, a central component of the RNA-induced silencing complex (RISC). Further work has shown that pathogenic LRRK2 inhibits let-7 (a miRNA) and miR-184 and this results in the upregulation of two transcription factors E2F1 and DP; a defect connected to locomotor activity defects in flies (Gehrke et al., 2010). Interestingly, the expression of SNCA mRNA is negatively regulated by at least two microRNAs, miR-7 and miR-153 (Doxakis, 2010; Junn et al., 2009) and DJ1 and Parkin expression has also been suggested to be connected to reduced miR-34b/c expression in late stage PD brain samples (Miñones-Moyano et al., 2011). "
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    ABSTRACT: Parkinson's disease is an incurable neurodegenerative disease. Most cases of the disease are of sporadic origin, but about 10% of the cases are familial. The genes thus far identified in Parkinson's disease are well conserved. Drosophila is ideally suited to study the molecular neuronal cell biology of these genes and the pathogenic mutations in Parkinson's disease. Flies reproduce fast and their elaborate and modern genetic tools in combination with their small size allows researchers to analyze identified cells and neurons in large numbers of animals. Furthermore, fruit flies recapitulate many of the organellar and molecular defects also seen in patients, and these defects often result in clear phenotypes also at the level of locomotion and behavior, facilitating genetic modifier screens. Hence, Drosophila has played a prominent role in Parkinson's disease research and has provided invaluable insight into the molecular mechanisms of this disease. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Feb 2015 · Experimental Neurology
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