Microarray expression analysis of human dopaminergic neuroblastoma cells after RNA interference of SNCA — A key player in the pathogenesis of Parkinson's disease

Abstract The pre-synaptic protein α-synuclein is a key player in the pathogenesis of Parkinson's disease (PD). Misfolded α-synuclein protofibrils accumulate and serve as seed structures that cause numerous proteins in the cytoplasm of neuronal cells to aggregate into so-called Lewy bodies. Furthermore, both missense mutations and multiplications of the SNCA gene lead to autosomal dominant forms of familial PD. However, the exact biological role of α-synuclein in normal brains remains elusive. To gain more insight into the normal function of this protein, we evaluated changes in whole genome expression in dopaminergic neuroblastoma cells (SH-SY5Y) caused by reductions of 90% in α-synuclein RNA levels and of 59% in α-synuclein protein levels as a result of RNA interference. The expression of 361 genes was altered at least ± 1.5-fold by the RNA interference, with 82 up-regulated and 279 down-regulated. The differentially expressed gene products are involved in the regulation of transcription, cell cycle, protein degradation, apoptosis, neurogenesis, and lipid metabolism. To examine the influence of SNCA down-regulation by RNAi on apoptosis, we performed cell death assays using different stress triggers. The changes observed in the expression profile of dopaminergic neuronal cells following reduction of SNCA expression warrant studies to investigate the role of signaling cascades in familial and idiopathic PD.