Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila

Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-Machi, Aoba-ku, Sendai 980-8575, Japan.
Human Molecular Genetics (Impact Factor: 6.68). 10/2010; 19(19):3747-58. DOI: 10.1093/hmg/ddq289
Source: PubMed

ABSTRACT Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO. Importantly, FoxO mutants that were resistant to LRRK2/dLRRK-induced phosphorylation suppressed this neurotoxicity. Moreover, we have determined that FoxO targets hid and bim in Drosophila and human, respectively, are responsible for the LRRK2/dLRRK-mediated cell death. These data suggest that the cell death molecules regulated by FoxO are key factors during the neurodegeneration in LRRK2-linked PD.

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Available from: Katerina Venderova, Aug 10, 2015
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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. · 2.24 Impact Factor
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    • "Therefore, foxo overexpression spared neurite pruning, but the growth (or maintenance) of adult-specific neurites was largely blocked, and many neurons subsequently disappeared altogether or ceased to express bursicon and ccap-Gal4. Because foxo overexpression under the bursicon-Gal4 driver and all other IIS manipulations with the ccap-Gal4 driver (below) did not result in substantial cell loss, we did not determine whether the loss in ccap.FOXO animals was due to possible neurotoxic functions of FOXO (Kanao et al., 2010; Siegrist et al., 2010). "
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    ABSTRACT: Although the growth capacity of mature neurons is often limited, some neurons can shift through largely unknown mechanisms from stable maintenance growth to dynamic, organizational growth (e.g. to repair injury, or during development transitions). During insect metamorphosis, many terminally differentiated larval neurons undergo extensive remodeling, involving elimination of larval neurites and outgrowth and elaboration of adult-specific projections. Here, we show in the fruit fly, Drosophila melanogaster (Meigen), that a metamorphosis-specific increase in insulin signaling promotes neuronal growth and axon branching after prolonged stability during the larval stages. FOXO, a negative effector in the insulin signaling pathway, blocked metamorphic growth of peptidergic neurons that secrete the neuropeptides CCAP and bursicon. RNA interference and CCAP/bursicon cell-targeted expression of dominant-negative constructs for other components of the insulin signaling pathway (InR, Pi3K92E, Akt1, S6K) also partially suppressed the growth of the CCAP/bursicon neuron somata and neurite arbor. In contrast, expression of wild-type or constitutively active forms of InR, Pi3K92E, Akt1, Rheb, and TOR, as well as RNA interference for negative regulators of insulin signaling (PTEN, FOXO), stimulated overgrowth. Interestingly, InR displayed little effect on larval CCAP/bursicon neuron growth, in contrast to its strong effects during metamorphosis. Manipulations of insulin signaling in many other peptidergic neurons revealed generalized growth stimulation during metamorphosis, but not during larval development. These findings reveal a fundamental shift in growth control mechanisms when mature, differentiated neurons enter a new phase of organizational growth. Moreover, they highlight strong evolutionarily conservation of insulin signaling in neuronal growth regulation.
    Biology Open 12/2013; 3(1). DOI:10.1242/bio.20136437 · 2.42 Impact Factor
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    • "Our study supports emerging data, which suggest that FoxO3A is a key mediator of the progressive neuronal cell loss associated with neurodegeneration and with other disorders of the nervous system. For example, increased FoxO3a has been found localized to Lewy bodies and Lewy neurites in Parkinson's disease brain tissue (Su et al. 2009) and activation of FoxO by LRRK2, associated with autosomal-dominant late-onset Parkinson's disease, enhances neuronal cell death in Drosophila (Kanao et al. 2010). With respect to Alzheimer's disease, inactivation of FoxO3a activity is correlated with reduced Alzheimer's disease-like pathology and with preservation of spatial reference memory in Tg2576 mice (Qin et al. 2008). "
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    ABSTRACT: The Forkhead transcription factor, FoxO3a induces genomic death responses in neurones following translocation from the cytosol to the nucleus. Nuclear translocation of FoxO3a is triggered by trophic factor withdrawal, oxidative stress and the stimulation of extrasynaptic NMDA receptors. Receptor activation of phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathways retains FoxO3a in the cytoplasm, thereby inhibiting the transcriptional activation of death-promoting genes. We hypothesized that phenolic antioxidants such as tert-Butylhydroquinone (tBHQ), which is known to stimulate PI3K-Akt signalling, would inhibit FoxO3a translocation and activity. Treatment of cultured cortical neurones with NMDA increased the nuclear localization of FoxO3a, reduced the phosphorylation of FoxO3a, increased caspase activity and up-regulated Fas ligand expression. In contrast the phenolic antioxidant, tBHQ, caused retention of FoxO3a in the cytosol coincident with enhanced PI3K- dependent phosphorylation of FoxO3a. tBHQ-induced nuclear exclusion of FoxO3a was associated with reduced FoxO-mediated transcriptional activity. Exposure of neurones to tBHQ inhibited NMDA-induced nuclear translocation of FoxO3a, prevented NMDA-induced up-regulation of FoxO-mediated transcriptional activity, blocked caspase activation and protected neurones from NMDA-induced excitotoxic death. Collectively, these data suggest that phenolic antioxidants such as tBHQ oppose stress-induced activation of FoxO3a and therefore have potential neuroprotective utility in neurodegeneration.
    Journal of Neurochemistry 07/2012; 123(1):182-91. DOI:10.1111/j.1471-4159.2012.07877.x · 4.24 Impact Factor
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