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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    • "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.
    Acta neurobiologiae experimentalis 04/2015; 75:1-26. · 1.29 Impact Factor
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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.
    Experimental Neurology 02/2015; DOI:10.1016/j.expneurol.2015.02.020 · 4.70 Impact Factor
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    • "LRRK2 encodes a large multi-domain protein characterized by leucine-rich repeats, a GTPase domain and a kinase domain (Bosgraaf and Van Haastert, 2003). The cellular functions of LRRK2 remain unclear because it has been linked to multiple diverse cellular processes, including mitochondrial function (Smith et al., 2005), regulation of transcription (Kanao et al., 2010) and translation (Gehrke et al., 2010; Imai et al., 2008; Martin et al., 2014), Golgi protein sorting (Sakaguchi-Nakashima et al., 2007), apoptosis (Ho et al., 2009), and regulation of the dynamics of actin (Jaleel et al., 2007; Parisiadou et al., 2009) and microtubules (Gandhi et al., 2008; Gillardon, 2009; Kett et al., 2012; Lin et al., 2009). Understanding the normal cellular functions of LRRK2 is vital because the mechanisms mediating the pathogenicity of mutant forms of LRRK2 are likely to be related to the physiological functions of the wild-type protein. "
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    ABSTRACT: Mutations in LRRK2 cause a dominantly inherited form of Parkinson's disease (PD), and are the most common known genetic determinant of PD. As inhibitor-based therapies targeting LRRK2 have emerged as a key therapeutic strategy in PD, understanding the consequences of inhibiting the normal cellular functions of LRRK2 is vital. Despite much interest, the physiologic functions of LRRK2 remain unclear. Several recent studies have linked the toxicity caused by overexpression of pathogenic mutant forms of LRRK2 to defects in the endolysosomal and autophagy pathways, raising the question of whether endogenous LRRK2 might play a role in these processes. Here we report the characterization of multiple novel nonsense alleles in the Drosophila LRRK2 homolog lrrk. Using these alleles, we show that lrrk loss-of-function causes striking defects in the endolysosomal and autophagy pathways, including accumulation of markedly enlarged lysosomes that are laden with undigested contents, consistent with a defect in lysosomal degradation. lrrk loss-of-function also results in accumulation of autophagosomes, as well as enlarged early endosomes laden with mono-ubiquitinated cargo proteins, suggesting an additional defect in lysosomal substrate delivery. Interestingly, the lysosomal abnormalities in these lrrk mutants can be suppressed by a constitutively active form of the small GTPase rab9, which promotes retromer-dependent recycling from late endosomes to the Golgi. Collectively, our data provides compelling evidence of a vital role for lrrk in lysosomal function and endolysosomal membrane transport in vivo, and suggests a link between lrrk and retromer-mediated endosomal recycling.
    Disease Models and Mechanisms 10/2014; 7(12). DOI:10.1242/dmm.017020 · 4.97 Impact Factor
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