p27Kip1 regulates alpha-synuclein expression
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Edurne Gallastegui1, Carla Domuro1, Joan Serratosa2, Alejandra Larrieux1, Laura Sin1, Jonatan Martinez1, Arnaud Besson3, José Manuel Morante-Redolat4, Serena Orlando1, Rosa Aligue1, Isabel Fariñas4, María Jesús Pujol1 and Oriol Bachs1
1Department of Biomedical Sciences, (CIBERONC), University of Barcelona, Barcelona, Spain
2Department of Cerebral Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain
3Cancer Research Center of Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France
4Departamento de Biología Celular, Biología Funcional y Antropología Física, ERI de Biotecnología y Biomedicina, (CIBERNED), Universidad de Valencia, Valencia, Spain
Oriol Bachs, email: firstname.lastname@example.org
Keywords: p27Kip1; p21Cip1; E2F4; alpha synuclein; transcription
Received: September 27, 2017 Accepted: February 27, 2018 Published: March 27, 2018
Alpha-synuclein (α-SYN) is the main component of anomalous protein aggregates (Lewy bodies) that play a crucial role in several neurodegenerative diseases (synucleinopathies) like Parkinson’s disease and multiple system atrophy. However, the mechanisms involved in its transcriptional regulation are poorly understood. We investigated here the role of the cyclin-dependent kinase (Cdk) inhibitor and transcriptional regulator p27Kip1 (p27) in the regulation of α-SYN expression. We observed that selective deletion of p27 by CRISPR/Cas9 technology in neural cells resulted in increased levels of α-SYN. Knock-down of the member of the same family p21Cip1 (p21) also led to increased α-SYN levels, indicating that p27 and p21 collaborate in the repression of α-SYN transcription. We demonstrated that this repression is mediated by the transcription factor E2F4 and the member of the retinoblastoma protein family p130 and that it is dependent of Cdk activity. Chromatin immunoprecipitation analysis revealed specific binding sites for p27, p21 and E2F4 in the proximal α-SYN gene promoter. Finally, luciferase assays revealed a direct action of p27, p21 and E2F4 in α-SYN gene expression. Our findings reveal for the first time a negative regulatory mechanism of α-SYN expression, suggesting a putative role for cell cycle regulators in the etiology of synucleinopathies.
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