title: The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway.
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.
authors: 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. chemabsp@unex.es
authors: José M
authors: JM
authors: Bravo-San Pedro
authors: Mireia
authors: M
authors: Niso-Santano
authors: Rubén
authors: R
authors: Gómez-Sánchez
authors: Elisa
authors: E
authors: Pizarro-Estrella
authors: Ana
authors: A
authors: Aiastui-Pujana
authors: Ana
authors: A
authors: Gorostidi
authors: Vicente
authors: V
authors: Climent
authors: Rakel
authors: R
authors: López de Maturana
authors: Rosario
authors: R
authors: Sanchez-Pernaute
authors: Adolfo
authors: A
authors: López de Munain
authors: José M
authors: JM
authors: Fuentes
authors: Rosa A
authors: RA
authors: González-Polo
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020935:MAP Kinase Signaling System; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; C040929:bafilomycin A1; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D006180:Proton-Translocating ATPases