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Hum Mol Genet. 2017 Jun 15;26(12):2231-2246. doi: 10.1093/hmg/ddx114.

Sodium butyrate rescues dopaminergic cells from alpha-synuclein-induced transcriptional deregulation and DNA damage.

Author information

1
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073, Göttingen, Germany.
2
Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal.
3
Department of Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), 37077?Göttingen, Germany.
4
Department of Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), 37077?Göttingen, Germany.
5
Department of Neuroscience and Disease, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
6
Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
7
Department of Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
8
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37077 Göttingen, Germany.
9
CEDOC - Chronic Diseases Research Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
10
Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.

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.

PMID:
28369321
DOI:
10.1093/hmg/ddx114
[Indexed for MEDLINE]

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