MPP+ increases α-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells

(x-Synuclein is a bra-in 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 (x-synuclein expression in a human neuroblastoma cell line, SH-SY5Y, caused by 5-100 muM 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 a-synuclein (more than threefold) in 4-day cultures was found in adherent cells treated with low concentrations of MPP+ (5 muM). 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. (C) 2002 Elsevier Science BY. All rights reserved.