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.

Download full-text


Available from: Katerina Venderova, Oct 03, 2015
24 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Despite the importance of LRRK2 for the pathogenesis in various diseases little is known about the cellular function of LRRK2. LRRK2 has been implicated in many different signaling pathways such as membrane trafficking [16], apoptosis [17], cytoskeletal remodeling [18], and transcriptional regulation [19]. LRRK2 was also described to modulate synaptic transmission [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is known to play a role in the pathogenesis of various diseases including Parkinson disease, morbus Crohn, leprosy and cancer. LRRK2 is suggested to be involved in a number of cell biological processes such as vesicular trafficking, transcription, autophagy and lysosomal pathways. Recent histological studies of lungs of LRRK2 knock-out (LRRK2 -/-) mice revealed significantly enlarged lamellar bodies (LBs) in alveolar type II (ATII) epithelial cells. LBs are large, lysosome-related storage organelles for pulmonary surfactant, which is released into the alveolar lumen upon LB exocytosis. In this study we used high-resolution, subcellular live-cell imaging assays to investigate whether similar morphological changes can be observed in primary ATII cells from LRRK2 -/- rats and whether such changes result in altered LB exocytosis. Similarly to the report in mice, ATII cells from LRRK2 -/- rats contained significantly enlarged LBs resulting in a >50% increase in LB volume. Stimulation of ATII cells with ATP elicited LB exocytosis in a significantly increased proportion of cells from LRRK2 -/- animals. LRRK2 -/- cells also displayed increased intracellular Ca(2+) release upon ATP treatment and significant triggering of LB exocytosis. These findings are in line with the strong Ca(2+)-dependence of LB fusion activity and suggest that LRRK2 -/- affects exocytic response in ATII cells via modulating intracellular Ca(2+) signaling. Post-fusion regulation of surfactant secretion was unaltered. Actin coating of fused vesicles and subsequent vesicle compression to promote surfactant expulsion were comparable in cells from LRRK2 -/- and wt animals. Surprisingly, surfactant (phospholipid) release from LRRK2 -/- cells was reduced following stimulation of LB exocytosis possibly due to impaired LB maturation and surfactant loading of LBs. In summary our results suggest that LRRK2 -/- affects LB size, modulates intracellular Ca(2+) signaling and promotes LB exocytosis upon stimulation of ATII cells with ATP.
    PLoS ONE 01/2014; 9(1):e84926. DOI:10.1371/journal.pone.0084926 · 3.23 Impact Factor
Show more