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

被引：118

作者：

Bravo-San Pedro, Jose M. ^{[1
]}

Niso-Santano, Mireia ^{[1
]}

Gomez-Sanchez, Ruben ^{[1
]}

Pizarro-Estrella, Elisa ^{[1
]}

Aiastui-Pujana, Ana ^{[2
,3
]}

Gorostidi, Ana ^{[2
,3
]}

Climent, Vicente ^{[4
]}

Lopez de Maturana, Rakel ^{[5
]}

Sanchez-Pernaute, Rosario ^{[5
]}

Lopez de Munain, Adolfo ^{[6
]}

Fuentes, Jose M. ^{[1
]}

Gonzalez-Polo, Rosa A. ^{[1
]}

机构：

[1] Univ Extremadura, Dept Bioquim Biol & Mol Genet & E Enfermeria & TO, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Avda Univ S-N, Caceres 10003, Spain

[2] Inst Biodonostia, Neurosci Area, San Sebastian 20014, Spain

[3] CIBERNED, San Sebastian 20014, Spain

[4] Univ Extremadura, Dept Anat & Embriol Humana, Fac Med, Badajoz 06071, Spain

[5] Fdn Inbiomed, Lab Celulas Madre & Neurorreparac, San Sebastian 20009, Spain

[6] Hosp Donostia, Serv Neurol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Inst Biodonostia, San Sebastian 20014, Spain

来源：

CELLULAR AND MOLECULAR LIFE SCIENCES | 2013年 / 70卷 / 01期

关键词：

Autophagy; LRRK2; G2019S; ERK; Parkinson's disease; REPEAT KINASE 2; NEUROBLASTOMA SH-SY5Y CELLS; ALPHA-SYNUCLEIN AGGREGATION; PARAQUAT-INDUCED AUTOPHAGY; PARKINSONS-DISEASE; REGULATES AUTOPHAGY; HT-29; CELLS; DEATH; PROTEINS; STRESS;

D O I：

10.1007/s00018-012-1061-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：121 / 136

页数：16

共 61 条

[1] LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model [J].