2024-03-28T18:03:22Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/2061512021-12-27T16:53:40Zcom_10261_105com_10261_1col_10261_358
CCAAT/enhancer binding protein δ is a transcriptional repressor of α-synuclein
Valente, Tony
Dentesano, Guido
Ezquerra, Mario
Fernández-Santiago, Rubén
Martinez-Martin, Jonatan
Gallastegui, Edurne
Domuro, Carla
Compta, Yaroslau
Martí, María-José
Bachs, Oriol
Márquez-Kisinousky, Leonardo
Straccia, Marco
Solà, Carme
Saura, Josep
Instituto de Salud Carlos III
European Commission
Fernández-Santiago, Rubén [0000-0002-4582-0702]
Neurological disorders
Neuroscience
α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson’s disease. Elevated α-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) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ 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/EBPβ and δ regulate the expression of SNCA. We first observed that α-synuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of α-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/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ 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/EBPδ as an important repressor of SNCA transcription and suggests 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 for these neurological disorders.
2020-04-01T11:44:53Z
2020-04-01T11:44:53Z
2020-02
2020-04-01T11:44:54Z
artículo
Cell Death and Differentiation 27: 509-524 (2020)
http://hdl.handle.net/10261/206151
10.1038/s41418-019-0368-8
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100000780
31209363
Postprint
http://dx.doi.org/10.1038/s41418-019-0368-8
Sí
openAccess
Springer Nature