1. Sodium butyrate rescues dopaminergic cells from alpha-synuclein-induced transcriptional deregulation and DNA damage
- Author
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Ashish Rajput, Raquel Pinho, Cemil Kerimoglu, Magali Hennion, Éva M. Szegö, Stefan Bonn, Pauline Wales, Anna Lena Schütz, Maria Angeliki S. Pavlou, Ellen Gerhardt, Andre Fischer, Isabel Paiva, Ana Cristina Rego, and Tiago F. Outeiro
- Subjects
0301 basic medicine ,DNA damage ,medicine.drug_class ,DNA repair ,Cell Culture Techniques ,metabolism [Parkinson Disease] ,Gene Expression ,genetics [Gene Expression Regulation] ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,genetics [Gene Expression] ,Dopaminergic Cell ,ddc:570 ,Genetics ,Transcriptional regulation ,medicine ,Humans ,metabolism [alpha-Synuclein] ,Molecular Biology ,Genetics (clinical) ,Regulation of gene expression ,biology ,Dopaminergic Neurons ,Histone deacetylase inhibitor ,metabolism [Dopaminergic Neurons] ,Parkinson Disease ,Sodium butyrate ,General Medicine ,Molecular biology ,3. Good health ,Cell biology ,030104 developmental biology ,Histone ,Gene Expression Regulation ,chemistry ,biology.protein ,genetics [alpha-Synuclein] ,alpha-Synuclein ,metabolism [Butyric Acid] ,Butyric Acid ,physiopathology [Parkinson Disease] ,030217 neurology & neurosurgery ,DNA Damage - Abstract
Alpha-synuclein (aSyn) is considered a major culprit in Parkinson's disease (PD) pathophysiology. However, the precise molecular function of the protein remains elusive. Recent evidence suggests that aSyn may play a role on transcription regulation, possibly by modulating the acetylation status of histones. Our study aimed at evaluating the impact of wild-type (WT) and mutant A30P aSyn on gene expression, in a dopaminergic neuronal cell model, and decipher potential mechanisms underlying aSyn-mediated transcriptional deregulation. We performed gene expression analysis using RNA-sequencing in Lund Human Mesencephalic (LUHMES) cells expressing endogenous (control) or increased levels of WT or A30P aSyn. Compared to control cells, cells expressing both aSyn variants exhibited robust changes in the expression of several genes, including downregulation of major genes involved in DNA repair. WT aSyn, unlike A30P aSyn, promoted DNA damage and increased levels of phosphorylated p53. In dopaminergic neuronal cells, increased aSyn expression led to reduced levels of acetylated histone 3. Importantly, treatment with sodium butyrate, a histone deacetylase inhibitor (HDACi), rescued WT aSyn-induced DNA damage, possibly via upregulation of genes involved in DNA repair. Overall, our findings provide novel and compelling insight into the mechanisms associated with aSyn neurotoxicity in dopaminergic cells, which could be ameliorated with an HDACi. Future studies will be crucial to further validate these findings and to define novel possible targets for intervention in PD.
- Published
- 2017