Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila.
Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO. Importantly, FoxO mutants that were resistant to LRRK2/dLRRK-induced phosphorylation suppressed this neurotoxicity. Moreover, we have determined that FoxO targets hid and bim in Drosophila and human, respectively, are responsible for the LRRK2/dLRRK-mediated cell death. These data suggest that the cell death molecules regulated by FoxO are key factors during the neurodegeneration in LRRK2-linked PD.
Kanao
Tomoko
T
Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-Machi, Aoba-ku, Sendai 980-8575, Japan.
Venderova
Katerina
K
Park
David S
DS
Unterman
Terry
T
Lu
Bingwei
B
Imai
Yuzuru
Y
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D002470:Cell Survival; D004298:Dopamine / Q000378:metabolism; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development / Q000648:ultrastructure; D005123:Eye / Q000201:enzymology / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008136:Longevity; D008565:Membrane Proteins / Q000378:metabolism; D008938:Mitosis; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009479:Neuropeptides / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; C108880:HID protein, Drosophila; D008565:Membrane Proteins; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; C543697:LRRK protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine