| RRC ID |
21882
|
| 著者 |
Kanao T, Sawada T, Davies SA, Ichinose H, Hasegawa K, Takahashi R, Hattori N, Imai Y.
|
| タイトル |
The nitric oxide-cyclic GMP pathway regulates FoxO and alters dopaminergic neuron survival in Drosophila.
|
| ジャーナル |
PLoS One
|
| Abstract |
Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a Drosophila model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines Drosophila genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and Drosophila orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A Drosophila FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD.
|
| 巻・号 |
7(2)
|
| ページ |
e30958
|
| 公開日 |
2012-2-29
|
| DOI |
10.1371/journal.pone.0030958
|
| PII |
PONE-D-11-18262
|
| PMID |
22393355
|
| PMC |
PMC3290610
|
| MeSH |
Animals
Biochemistry / methods
Cell Line
Cell Survival
Cyclic GMP / metabolism*
Dopaminergic Neurons / cytology*
Drosophila / metabolism*
Drosophila Proteins / metabolism*
Female
Forkhead Transcription Factors / metabolism*
Guanylate Cyclase / metabolism
HEK293 Cells
Humans
Mice
Models, Biological
Models, Genetic
Mutation
Neurodegenerative Diseases / metabolism
Neurons / metabolism
Nitric Oxide / metabolism*
Nitric Oxide Synthase / metabolism
Phosphorylation
Receptors, Cytoplasmic and Nuclear / metabolism
Signal Transduction
Soluble Guanylyl Cyclase
|
| IF |
2.74
|
| 引用数 |
13
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ショウジョウバエ |
8091R-2 |
