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Status |
Public on Mar 31, 2017 |
Title |
Sodium butyrate ameliorates aSyn-induced transcription deregulation and DNA damage |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Alpha-synuclein (aSyn) is widely portrayed as the main culprit on 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 to evaluate the impact of wild-type (WT) and mutant A30P aSyn on gene expression, in a dopaminergic neuronal cell model, and decipher potential mechanisms behind aSyn-induced transcriptional deregulation. We performed RNA-sequencing in Lund Human Mesencephalic (LUHMES) cells expressing endogenous (control) or increased WT or A30P aSyn levels. Compared to control, LUHMES cells expressing aSyn exhibited robust changes in the expression of several genes, including downregulation of major genes involved in DNA repair. Expressing WT aSyn, unlike A30P aSyn, led to increased DNA damage and phosphorylated p53 levels. In our dopaminergic neuronal cell model, aSyn expression promoted lower histone 3 acetylation levels. Excitingly, treatment with sodium butyrate, a histone deacetylase inhibitor (HDACi), was able to rescue WT aSyn-induced DNA damage, possibly via upregulation of genes involved in DNA repair. Overall, our findings provide compelling, pioneer evidence for a novel mechanism associated with aSyn neurotoxicity in dopaminergic cells, which could be ameliorated with a HDACi. Prospective studies will be crucial to further validate these findings and its relevance to our knowledge of PD.
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Overall design |
RNA from Lund Human Mesencephalic (LUHMES) cells was used to assess the impact of alpa-synuclein (aSyn) on cellular transcription. For this purpose, three different cell lines were generated. Briefly, proliferating LUHMES cells were infected with equimolar amounts of lentiviral particles encoding for: IRES-GFP (samples set C); full-length human wild-type (WT) aSyn (SNCA, NM_000345), WT aSyn-IRES-GFP (samples set E) or familial mutant A30P aSyn, A30P aSyn-IRES-GFP (samples set A). Positive green fluorescent cells were selected by fluorescence activated cell sorting. Three independent replicates were generated for each cell line. Total RNA from differentiated LUHMES cells, at differentiation day 8, was extracted and purified using the RNeasy mini kit (Qiagen), according to the instructions of the manufacturer.
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Contributor(s) |
Paiva I, Pinho R, Hennion M, Rajput A, Capece V, Kerimoglu C, Wales P, Gerhardt E, Szegő É, Pavlou MA, Fischer A, Bonn S, Rego C, Outeiro TF |
Citation missing |
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Submission date |
Oct 24, 2016 |
Last update date |
May 15, 2019 |
Contact name |
Ashish Rajput |
E-mail(s) |
ashish.medbt@gmail.com
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Phone |
+495513961173
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Organization name |
German Center for Neurodegenerative Diseases (DZNE)
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Department |
Research Group for Computational Systems Biology
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Lab |
Bonn-lab
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Street address |
Von-Siebold-Straße 3A
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City |
Göttingen |
State/province |
Niedersachsen |
ZIP/Postal code |
37075 |
Country |
Germany |
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Platforms (1) |
GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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Samples (9)
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Relations |
BioProject |
PRJNA350311 |
SRA |
SRP091992 |
Supplementary file |
Size |
Download |
File type/resource |
GSE89115_DEG.xls.gz |
13.5 Mb |
(ftp)(http) |
XLS |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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