alpha-Synuclein is a major protein component deposited in Lewy bodies and Lewy 
neurites that is extensively phosphorylated at Ser(129), although its role in 
neuronal degeneration is still elusive. In this study, several apoptotic 
pathways were examined in alpha-synuclein-overexpressing SH-SY5Y cells. 
Following the treatment with rotenone, a mitochondrial complex I inhibitor, wild 
type alpha-synuclein-overexpressing cells demonstrated intracellular 
aggregations, which shared a number of features with Lewy bodies, although cells 
overexpressing the S129A mutant, in which phosphorylation at Ser(129) was 
blocked, showed few aggregations. In wild typealpha-synuclein cells treated with 
rotenone, the proportion of phosphorylated alpha-synuclein was about 1.6 times 
higher than that of untreated cells. Moreover, induction of unfolded protein 
response (UPR) markers was evident several hours before the induction of 
mitochondrial disruption and caspase-3 activation. Eukaryotic initiation factor 
2alpha, a member of the PERK pathway family, was remarkably activated at early 
phases. On the other hand, the S129A mutant failed to activate UPR. Casein 
kinase 2 inhibitor, which decreased alpha-synuclein phosphorylation, also 
reduced UPR activation. The alpha-synuclein aggregations were colocalized with a 
marker for the endoplasmic reticulum-Golgi intermediate compartment. Taken 
together, it seems plausible that alpha-synuclein toxicity is dependent on the 
phosphorylation at Ser(129) that induces the UPRs, possibly triggered by the 
disturbed endoplasmic reticulum-Golgi trafficking.