CCAAT/enhancer binding protein ? is a transcriptional repressor of ?-synuclein.

ABSTRACT: ?-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated ?-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) ? and ? are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBP? overexpression increases SNCA expression in neuroblastoma cells and putative C/EBP? and ? 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? and ? regulate the expression of SNCA. We first observed that ?-synuclein CNS expression was not affected by C/EBP? deficiency but it was markedly increased in C/EBP?-deficient mice. This prompted us to characterize further the role of C/EBP? in SNCA transcription. C/EBP? absence led to the in vivo increase of ?-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? binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBP? 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? as an important repressor of SNCA transcription and suggests that reduced C/EBP? neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBP? activity a potential pharmacological target for these neurological disorders.

SUBMITTER: Valente T 

PROVIDER: S-EPMC7206087 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature