CCAAT/enhancer binding protein δ is a transcriptional repressor of α-synuclein

alpha-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated alpha-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) beta and delta are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBP beta overexpression increases SNCA expression in neuroblastoma cells and putative C/EBP beta and delta binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBP beta and delta regulate the expression of SNCA. We first observed that alpha-synuclein CNS expression was not affected by C/EBP beta deficiency but it was markedly increased in C/EBP delta-deficient mice. This prompted us to characterize further the role of C/EBP delta in SNCA transcription. C/EBP delta absence led to the in vivo increase of alpha-synuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBP delta binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBP delta binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBP delta as an important repressor of SNCA transcription and suggests that reduced C/EBP delta neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBP delta activity a potential pharmacological target for these neurological disorders.