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: 6.39). 10/2010; 19(19):3747-58. DOI: 10.1093/hmg/ddq289
Source: PubMed


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.


Available from: Katerina Venderova
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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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    • "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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    • "To help dissect the molecular processes involved in PD pathology, we recently generated a Drosophila overexpressing human LRRK2 with a PD pathogenic I2020T mutation within the kinase domain [13]. This transgenic model has been successfully used by other researchers [14,15]. As shown previously by our team [13] and independently validated by others [16-18], expressing pathogenic mutant LRRK2 in Drosophila DA neurons recapitulates many of the cardinal features of PD, including the loss of DA neurons and locomotor deficits [13]. "
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    ABSTRACT: Background Parkinson’s disease (PD) is the most common movement neurodegenerative movement disorder. An incomplete understanding of the molecular pathways involved in its pathogenesis impedes the development of effective disease-modifying treatments. To address this gap, we have previously generated a Drosophila model of PD that overexpresses PD pathogenic mutant form of the second most common causative gene of PD, Leucine-Rich Repeat Kinase 2 (LRRK2). Findings We employed this model in a genetic modifier screen and identified a gene that encodes for a core subunit of retromer – a complex essential for the sorting and recycling of specific cargo proteins from endosomes to the trans-Golgi network and cell surface. We present evidence that overexpression of the Vps35 or Vps26 component of the cargo-recognition subunit of the retromer complex ameliorates the pathogenic mutant LRRK2 eye phenotype. Furthermore, overexpression of Vps35 or Vps26 significantly protects from the locomotor deficits observed in mutant LRRK2 flies, as assessed by the negative geotaxis assay, and rescues their shortened lifespan. Strikingly, overexpressing Vps35 alone protects from toxicity of rotenone, a neurotoxin commonly used to model parkinsonism, both in terms of lifespan and locomotor activity of the flies, and this protection is sustained and even augmented in the presence of mutant LRRK2. Finally, we demonstrate that knocking down expression of Vps35 in dopaminergic neurons causes a significant locomotor impairment. Conclusions From these results we conclude that LRRK2 plays a role in the retromer pathway and that this pathway is involved in PD pathogenesis.
    Molecular Neurodegeneration 06/2014; 9(1):23. DOI:10.1186/1750-1326-9-23 · 6.56 Impact Factor
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