論文 - 詳細
| RRC ID | 28601 |
|---|---|
| 著者 | Kanao T, Venderova K, Park DS, Unterman T, Lu B, Imai Y. |
| タイトル | Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. |
| ジャーナル | Hum Mol Genet |
| Abstract |
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. |
| 巻・号 | 19(19) |
| ページ | 3747-58 |
| 公開日 | 2010-10-1 |
| DOI | 10.1093/hmg/ddq289 |
| PII | ddq289 |
| PMID | 20624856 |
| MeSH | Amino Acid Sequence Animals Apoptosis* Apoptosis Regulatory Proteins / metabolism Bcl-2-Like Protein 11 Cell Line Cell Survival Dopamine / metabolism Drosophila Proteins / chemistry Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / cytology Drosophila melanogaster / enzymology* Drosophila melanogaster / growth & development Drosophila melanogaster / ultrastructure Eye / enzymology Eye / growth & development Eye / pathology Eye / ultrastructure Forkhead Transcription Factors / chemistry Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism* Humans Longevity Membrane Proteins / metabolism Mitosis* Molecular Sequence Data Nerve Degeneration / metabolism Nerve Degeneration / pathology Neurons / metabolism Neurons / pathology* Neurons / ultrastructure Neuropeptides / metabolism Phosphorylation Protein Serine-Threonine Kinases / metabolism* Proto-Oncogene Proteins / metabolism Transcription, Genetic |
| IF | 5.101 |
| 引用数 | 64 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY GENETICS & HEREDITY |
| リソース情報 | |
| ショウジョウバエ | |
| 遺伝子材料 | pUAST-dFoxO (RDB07961) pBluescriptSKII(+)-dFoxO (RDB07960) |