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Title

The transcription factor C/EBPd represses a-synuclein transcription: potential pathogenic effects of C/EBPd deficiency in Parkinson's disease

AuthorsValente, Tony ; Dentesano, Guido ; Ezquerra, Mario; Fernández-Santiago, Rubén; Compta, Yaroslau; Martí, María-José; Bachs, Oriol; Gallastegui, Edurne; Domuro, Carla; Márquez-Kisinousky, Leonardo ; Straccia, Marco ; Solà, Carme ; Saura, Josep
Issue Date12-Nov-2018
CitationXI Simposi de Neurobiologia (2018)
Abstractα-Synuclein, one of the most abundant proteins in neuronal cytosol, plays an ill-defined role in neurotransmitter release and synaptic vesicle trafficking and is the main component of Lewy bodies, the intracellular protein aggregates that are considered the histological hallmark of Parkinson’s disease. High α-synuclein levels are associated with increased risk for Parkinson's disease. Surprisingly little is known about the regulation of transcription of the human αsynuclein (SNCA) gene. CCAAT/enhancer binding protein δ (C/EBPδ) is a b-zip transcription factor expressed in the CNS that plays distinct roles in neurons and glial cells. C/EBPδ binding boxes are present in the SNCA genomic region, suggesting that this transcription factor could regulate SNCA transcription. The aim of this study was to determine if C/EBPδ regulates the expression of SNCA. We first observed that α-synuclein expression was markedly increased in C/EBPδ-deficient mice in several brain regions, both at mRNA and protein level. α-synuclein levels were also increased in C/EBPδ-deficient primary neuronal, but not glial, cultures. In accordance, C/EBPδ overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced α-synuclein expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans. Finally, decreased C/EBPδ expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between α-synuclein and C/EBPδ levels. This study demonstrates for the first time that C/EBPδ is a potent repressor of SNCA transcription. These findings suggest that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson’s disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target to treat these neurological disorders
DescriptionTrabajo presentado en el XI Simposi de Neurobiologia: Future technical advances, organizado por la Socitat Catalana de Biologia, en Barcelona, los días 12 y 13 de noviembre de 2018
URIhttp://hdl.handle.net/10261/177661
Appears in Collections:(IIBB) Comunicaciones congresos
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