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

Human Molecular Genetics
Tomoko KanaoYuzuru Imai

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.

References

Oct 25, 2001·Proceedings of the National Academy of Sciences of the United States of America·T OsterwalderH Keshishian
May 8, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Marie StahlRené H Medema
Mar 27, 2004·Transfusion·Kalpana S Reddy, Peter L Perrotta
Sep 29, 2004·Hypertension·Anil K Bidani, Karen A Griffin
Nov 3, 2004·Proceedings of the National Academy of Sciences of the United States of America·Blanka Rogina, Stephen L Helfand
Nov 16, 2004·Neuron·Coro Paisán-RuízAndrew B Singleton
Nov 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Andrew B WestTed M Dawson
Dec 3, 2005·Human Molecular Genetics·Christian Johannes GloecknerMarius Ueffing
Dec 6, 2005·Gene Expression Patterns : GEP·Marco F M HoekmanJ Peter H Burbach
Apr 18, 2006·Trends in Neurosciences·Ignacio F MataKathleen A Gallo
Jul 5, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yufeng YangBingwei Lu
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Günter U HöglingerStéphane Hunot
May 25, 2007·Nature Reviews. Molecular Cell Biology·Armando van der Horst, Boudewijn M T Burgering
Jul 19, 2008·Neuroscience Letters·Baek-Soo HanKwang-Soo Kim
Aug 18, 2009·Nature Neuroscience·Luke S TainAlexander J Whitworth
Oct 15, 2009·The Journal of Biological Chemistry·Saurabh SenAndrew B West
Nov 17, 2009·Nature Genetics·Javier Simón-SánchezThomas Gasser

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Citations

Mar 24, 2012·Current Neurology and Neuroscience Reports·Elpida Tsika, Darren J Moore
Jun 17, 2011·Expert Reviews in Molecular Medicine·Azad Kumar, Mark R Cookson
Oct 19, 2012·Nature·Guang-Hui LiuJuan Carlos Izpisua Belmonte
Sep 18, 2012·Antioxidants & Redox Signaling·Paraskevi Charitou, Boudewijn M T Burgering
Dec 16, 2011·Human Molecular Genetics·Mark W DodsonMing Guo
Mar 7, 2012·Cold Spring Harbor Perspectives in Medicine·Lauren R Kett, William T Dauer
Apr 23, 2011·Parkinson's Disease·Verónica Muñoz-Soriano, Nuria Paricio
Jun 5, 2013·Neurochemical Research·Hardy J Rideout, Leonidas Stefanis
Feb 9, 2012·The Journal of Cell Biology·Inna V Nechipurenko, Heather T Broihier
Feb 11, 2011·Trends in Cell Biology·Daniel C Berwick, Kirsten Harvey
Dec 7, 2013·The European Journal of Neuroscience·Kiren UbhiEliezer Masliah
Sep 29, 2011·Neurobiology of Disease·Ravi S AkundiHansruedi Büeler
Nov 12, 2013·Expert Opinion on Therapeutic Targets·Sharon L ChanEng-King Tan
Feb 14, 2012·Biochemical and Biophysical Research Communications·Yoon Ki HongKyoung Sang Cho
May 14, 2014·Neurobiology of Aging·Arvind K ShuklaDebapratim Kar Chowdhuri
Apr 10, 2015·PloS One·Emmanouil RizosVassilios Zoumpourlis
Oct 21, 2014·PLoS Genetics·Xingyin LiuJulie Secombe
Aug 11, 2016·PLoS Genetics·Geetanjali ChawlaNicholas S Sokol
Oct 11, 2016·Proteomics·Un-Beom Kang, Jarrod A Marto
Jan 26, 2017·Scientific Reports·Zohreh HosseinzadehFlorian Lang
Jun 7, 2017·Journal of Cellular Biochemistry·Ji-Soo KimJin H Son
Mar 20, 2016·G3 : Genes - Genomes - Genetics·Janani IyerSanthosh Girirajan
Oct 31, 2018·International Journal of Molecular Sciences·Emi Nagoshi
Jul 1, 2017·Frontiers in Genetics·Malabika MaulikElena M Vayndorf

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