The nitric oxide-cyclic GMP pathway regulates FoxO and alters dopaminergic neuron survival in Drosophila

Kanao, T., Sawada, T., Davies, S. , Ichinose, H., Hasegawa, K., Takahashi, R., Hattori, N. and Imai, Y. (2012) The nitric oxide-cyclic GMP pathway regulates FoxO and alters dopaminergic neuron survival in Drosophila. PLoS ONE, 7(2), e30958. (doi: 10.1371/journal.pone.0030958) (PMID:22393355) (PMCID:PMC3290610)

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Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a <i>Drosophila</i> model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines <i>Drosophila</i> genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and <i>Drosophila</i> orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A <i>Drosophila</i> FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Davies, Professor Shireen
Authors: Kanao, T., Sawada, T., Davies, S., Ichinose, H., Hasegawa, K., Takahashi, R., Hattori, N., and Imai, Y.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:PLoS ONE
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in PLoS ONE 7(2):e30958
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
378481Exploration of cyclic 3', 5' guanosine monophosphate (cGMP) signalling dynamics in vivoShireen DaviesBiotechnology and Biological Sciences Research Council (BBSRC)BB/C000633/1Institute of Molecular Cell and Systems Biology