Prosurvival role of JAK/STAT and Akt signaling pathways in MPP+-induced apoptosis in neurons.
In the present study the role of JAK/STAT and Akt in apoptosis was evaluated in cerebellar granule cells after treatment with the mitochondrial toxin MPP(+). Firstly, we evaluated the role of the prosurvival Akt pathway in MPP(+)-induced apoptosis and found that MPP(+) rapidly reduced the phosphorylation of Akt at Ser473. Since PTEN is an upstream regulator of Akt, its inhibition with bpV(pic) (1-30 μM) should activate Akt, however, it did not attenuate CGC cell death mediated by MPP(+) but protected CGC from apoptosis mediated by S/K deprivation. We also demonstrated that after the treatment with the complex I inhibitor, the expression levels of STAT1 increased and the levels of STAT3 decreased at the time points tested (0.5-8h). Meanwhile, pharmacological inhibition of the JAK/STAT pathway with AG490 (10-40 μM) was neuroprotective, probably due to its antioxidant properties, the Jak2-inhibitor-II potentiated MPP(+) neurotoxicity. Collectively, our data indicate that the treatment of CGC with the neurotoxin MPP(+) decreased two prosurvival pathways: STAT3 and Akt. Meanwhile Akt activation, using a PTEN inhibitor, did not play a prominent role in neuroprotection; loss of STAT3 could be a signal pathway involved in neuroprotection against the Parkinsonian neurotoxin MPP(+).
Junyent
Felix
F
Institut de Biomedicina (IBUB), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.
Alvira
Daniel
D
Yeste-Velasco
Marc
M
de la Torre
Aurelio Vazquez
AV
Beas-Zarate
Carlos
C
Sureda
Francesc X
FX
Folch
Jaume
J
Pallàs
Mercè
M
Camins
Antoni
A
Verdaguer
Ester
E
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D015655:1-Methyl-4-phenylpyridinium