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The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway |
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| Authors: | José M. Bravo-San Pedro Mireia Niso-Santano Rubén Gómez-Sánchez Elisa Pizarro-Estrella Ana Aiastui-Pujana Ana Gorostidi Vicente Climent Rakel López de Maturana Rosario Sanchez-Pernaute Adolfo López de Munain José M. Fuentes Rosa A. González-Polo |
| Affiliation: | 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 2. Neuroscience Area, Instituto Biodonostia and CIBERNED, 20014, San Sebastián, Spain 3. Departamento de Anatomía y Embriología Humana, Facultad de Medicina, Universidad de Extremadura, 06071, Badajoz, Spain 4. Laboratorio de Células madre y Neurorreparación, Fundación Inbiomed, 20009, San Sebastián, Spain 5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Biodonostia, Servicio de Neurología, Hospital Donostia, 20014, San Sebastián, Spain |
| 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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