MPP+ increases alpha-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells.
Alpha-synuclein is a brain presynaptic protein that is linked to familiar early onset Parkinson's disease and it is also a major component of Lewy bodies in sporadic Parkinson's disease and other neurodegenerative disorders. Alpha-synuclein expression increases in substantia nigra of both MPTP-treated rodents and non-human primates, used as animal models of parkinsonism. Here we describe an increase in alpha-synuclein expression in a human neuroblastoma cell line, SH-SY5Y, caused by 5-100 microM MPP+, the active metabolite of MPTP, which induces apoptosis in SH-SY5Y cells after a 4-day treatment. We also analysed the activation of the MAPK family, which is involved in several cellular responses to toxins and stressing conditions. Parallel to the increase in alpha-synuclein expression we observed activation of MEK1,2 and ERK/MAPK but not of SAPK/JNK or p38 kinase. The inhibition of the ERK/MAPK pathway with U0126, however, did not affect the increase in alpha-synuclein. The highest increase in alpha-synuclein (more than threefold) in 4-day cultures was found in adherent cells treated with low concentrations of MPP+ (5 microM). Inhibition of ERK/MAPK reduced the damage caused by MPP+. We suggest that alpha-synuclein increase and ERK/MAPK activation have a prominent role in the cell mechanisms of rescue and damage, respectively, after MPP+ -treatment.
Gómez-Santos
Cristina
C
Unitat de Bioquímica, Departament Ciències Fisiològiques II, Campus Bellvitge, Universitat de Barcelona, c/. Feixa Llarga s/n, L'Hospitalet del Llobregat, E-08907 Barcelona, Spain.
Ferrer
Isidre
I
Reiriz
Julia
J
Viñals
Francesc
F
Barrachina
Marta
M
Ambrosio
Santiago
S
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000187:drug effects; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D051843:Synucleins; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D051844:alpha-Synuclein; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D019311:Staurosporine; D015655:1-Methyl-4-phenylpyridinium