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The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway

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Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a major cause of familial Parkinsonism, and the G2019S mutation of LRRK2 is one of the most prevalent mutations. The deregulation of autophagic processes in nerve cells is thought to be a possible cause of Parkinson’s disease (PD). In this study, we observed that G2019S mutant fibroblasts exhibited higher autophagic activity levels than control fibroblasts. Elevated levels of autophagic activity can trigger cell death, and in our study, G2019S mutant cells exhibited increased apoptosis hallmarks compared to control cells. LRRK2 is able to induce the phosphorylation of MAPK/ERK kinases (MEK). The use of 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a highly selective inhibitor of MEK1/2, reduced the enhanced autophagy and sensibility observed in G2019S LRRK2 mutation cells. These data suggest that the G2019S mutation induces autophagy via MEK/ERK pathway and that the inhibition of this exacerbated autophagy reduces the sensitivity observed in G2019S mutant cells.

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Abbreviations

Baf A1:

Bafilomycin A1

cDNA:

DNA complementary

CMFDA:

5-chloromethylfluorescein diacetate

Cyt c:

Cytochrome c

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

EBSS:

Earle’s balanced salt solution medium

ERK:

MAPK/extracellular signal-regulated protein kinase

ERM:

Ezrin/radixin/moesin

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

Ho:

Hoechst 33342

LAMP-2:

Lysosomal-associated membrane protein 2

LRRK2:

Leucine-rich repeat kinase 2

LTR:

LysoTracker Red DND99

MAPK:

Mitogen-activated protein kinase

MBP:

Myelin basic protein

MEK:

MAPK/ERK kinase

mTOR:

The mammalian target of rapamycin

PBS:

Phosphate buffered saline

PCR:

Polymerase chain reaction

PD:

Parkinson’s disease

PI:

Propidium iodide

ROS:

Reactive oxygen species

U0126:

1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene

Wt:

Wild-type

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Acknowledgments

The authors would like to thank P. Delgado, R. Ronco, S.M.S.Y. Diop, V. Llorente-Vera, J. Bragado, J. Correa, R. Tarazona, and R. Rodriguez for invaluable technical assistance. The authors also thank FUNDESALUD. José M. Bravo-San Pedro was supported by a Junta de Extremadura predoctoral fellowship. Mireia Niso-Santano was supported as a postdoctoral researcher by the University of Extremadura. Ruben Gómez-Sánchez was supported by a Spanish Ministerio de Educación predoctoral fellowship. Ana Aiastui-Pujana and Ana Gorostidi were supported by the Ilundain Fundazioa. Rosa-Ana González-Polo was supported by a “Miguel Servet” contract (ISCIII, Ministerio de Ciencia e Innovación, Spain). Dr. Sánchez-Pernaute received research support from the Ministerio de Ciencia e Innovación, Spain (SAF 2008-04615). Dr. López de Munain received research support from the Basque Government, Spain (SAIOTEK SA-2009/00071). Dr. González-Polo received research support from ISCIII (Ministerio de Ciencia e Innovación, Spain (CP0800010, PI11/0040) and FUNDESALUD (PRIS11014). Dr. José M. Fuentes received research support from the Ministerio de Ciencia e Innovación, Spain (SAF2010-14993), FUNDESALUD (PRIS10013, PRIS11019), CIBERNED (CB06/05/004) and Consejería, Economía, Comercio e Innovación Junta de Extremadura (GRU10054).

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Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular y Genética, E. Enfermería y T.O., Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universidad de Extremadura, Avda Universidad, s/n, 10003, Cáceres, Spain

    José M. Bravo-San Pedro, Mireia Niso-Santano, Rubén Gómez-Sánchez, Elisa Pizarro-Estrella, José M. Fuentes & Rosa A. González-Polo

  2. Neuroscience Area, Instituto Biodonostia and CIBERNED, 20014, San Sebastián, Spain

    Ana Aiastui-Pujana & Ana Gorostidi

  3. Departamento de Anatomía y Embriología Humana, Facultad de Medicina, Universidad de Extremadura, 06071, Badajoz, Spain

    Vicente Climent

  4. Laboratorio de Células madre y Neurorreparación, Fundación Inbiomed, 20009, San Sebastián, Spain

    Rakel López de Maturana & Rosario Sanchez-Pernaute

  5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Biodonostia, Servicio de Neurología, Hospital Donostia, 20014, San Sebastián, Spain

    Adolfo López de Munain

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  1. José M. Bravo-San Pedro
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  2. Mireia Niso-Santano
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  3. Rubén Gómez-Sánchez
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  5. Ana Aiastui-Pujana
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  6. Ana Gorostidi
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  7. Vicente Climent
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  8. Rakel López de Maturana
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  9. Rosario Sanchez-Pernaute
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  10. Adolfo López de Munain
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  11. José M. Fuentes
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  12. Rosa A. González-Polo
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Corresponding authors

Correspondence to José M. Fuentes or Rosa A. González-Polo.

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J. M. Fuentes and R. A. González-Polo contributed equally to this paper.

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Bravo-San Pedro, J.M., Niso-Santano, M., Gómez-Sánchez, R. et al. The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell. Mol. Life Sci. 70, 121–136 (2013). https://doi.org/10.1007/s00018-012-1061-y

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