title: Genetic dissection reveals that Akt is the critical kinase downstream of LRRK2 to phosphorylate and inhibit FOXO1, and promotes neuron survival.
abstract: Leucine-rich repeat kinase 2 (LRRK2) is a complex kinase and mutations in LRRK2 are perhaps the most common genetic cause of Parkinson's disease (PD). However, the identification of the normal physiological function of LRRK2 remains elusive. Here, we show that LRRK2 protects neurons against apoptosis induced by the Drosophila genes grim, hid and reaper. Genetic dissection reveals that Akt is the critical downstream kinase of LRRK2 that phosphorylates and inhibits FOXO1, and thereby promotes survival. Like human LRRK2, Drosophila lrrk also promotes neuron survival; lrrk loss-of-function mutant displays reduced cell numbers, which can be rescued by LRRK2 expression. Importantly, LRRK2 G2019S and LRRK2 R1441C mutants impair the ability of LRRK2 to activate Akt, and fail to prevent apoptotic death. Ectopic expression of a constitutive active form of Akt hence is sufficient to rescue this functional deficit. These data establish that LRRK2 can protect neurons from apoptotic insult through a survival pathway in which LRRK2 signals to activate Akt, and then inhibits FOXO1. These results might indicate that a LRRK-Akt therapeutic pathway to promote neuron survival and to prevent neurodegeneration in Parkinson's disease.
authors.affiliation: Institute of Systems Neuroscience, Department of Medical Science, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan and Brain Research Center, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Chia-Lung
authors.initials: CL
authors.lastname: Chuang
authors.affiliation: Institute of Systems Neuroscience, Department of Medical Science, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan and Brain Research Center, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Lu
authors.affiliation: Institute of Systems Neuroscience, Department of Medical Science, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan and Brain Research Center, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
authors.forename: Hung-Cheng
authors.initials: HC
authors.lastname: Wang
authors.affiliation: Institute of Systems Neuroscience, Department of Medical Science, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan and Brain Research Center, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan huiyun@life.nthu.edu.tw.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Chang
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C085126:FOXO1 protein, human; C495280:LRRK2 protein, human; C543697:LRRK protein, Drosophila