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

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

    OnderzoeksoutputAcademicpeer review

    128 Citaten (Scopus)

    Samenvatting

    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.

    Originele taal-2English
    Pagina's (van-tot)121-36
    Aantal pagina's16
    TijdschriftCellular and molecular life sciences
    Volume70
    Nummer van het tijdschrift1
    DOI's
    StatusPublished - jan.-2013

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