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 naive 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
