Functional dissection of the alpha-synuclein promoter: transcriptional regulation by ZSCAN21 and ZNF219.
Alpha-synuclein (SNCA) is an abundant neuronal protein involved in synaptic neurotransmission. SNCA expression levels have been strongly implicated in Parkinson's disease pathogenesis. We have previously demonstrated that in the PC12 cell line elements in intron 1 may mediate SNCA transcriptional regulation in response to neurotrophins. We have now identified transcription factor (TF) binding sites in intron 1 and the 5'-promoter of SNCA. A binding site for the TF zinc finger and SCAN domain containing (ZSCAN)21 in the 5'-region of intron 1 is required for intron 1 transcriptional activity. Small interfering RNA against ZSCAN21 inhibits activation in the luciferase assay and diminishes SNCA protein levels in naïve and neurotrophin-treated PC12 cells and in primary cultured cortical neurons, demonstrating that ZSCAN21 is a novel transcriptional regulator of SNCA in neuronal cells. The 5'-promoter of SNCA has a complex architecture, including multiple binding sites for the TF zinc finger protein (ZNF)219, which functions as both an activator and a repressor. Targeting ZSCAN21 or other TFs controlling SNCA transcriptional activity may provide novel therapeutic avenues not only for Parkinson's disease but also for other synucleopathies.
Clough
Richard Lee
RL
Division of Basic Neuroscience, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece. lclough@bioacademy.gr
Dermentzaki
Georgia
G
Stefanis
Leonidas
L
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007438:Introns / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D009414:Nerve Growth Factors / Q000502:physiology; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000502:physiology*; D016335:Zinc Fingers / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D015534:Trans-Activators; C413370:ZNF219 protein, human; C510393:ZSCAN21 protein, human; D051844:alpha-Synuclein