The accumulation of α-synuclein is the primary pathological hallmark of Parkinson's disease (PD). In PD patients, CpG demethylation of intron-1 has been reported to be associated with α-synuclein up-regulation. Environmental factor, for example neurotoxin, is a major etiological risk factor in PD pathogenesis. However, the role of CpG methylation in neurotoxin-induced PD has not been addressed completely yet. To explore CpG methylation associating with α-synuclein transcription and its underlying mechanisms in the neurotoxin-induced PD pathology, human neuroblastoma SH-SY5Y cells were treated with neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP). Results showed that MPP induced demethylation of the whole length of the CpG island around SNCA promoter, and both 6-OHDA and MPP resulted in up-regulation of SNCA transcription. The CpG demethylation around promoter resulted in up-regulation of SNCA transcriptional activity. In addition, 6-OHDA and MPP induced the reduced levels of DNA methyltransferase (DNMT) 3a and DNMT3b but not DNMT1. These data suggested that CpG demethylation was induced by MPP and might mediate up-regulation of SNCA transcription in neurotoxin-induced PD. And down-regulation of both DNMT3a and DNMT3b, but not DNMT1, might contribute to CpG demethylation of the SNCA promoter.
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