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Series GSE89115 Query DataSets for GSE89115
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
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.
 
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.
 
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
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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
Phone +495513961173
Organization name German Center for Neurodegenerative Diseases (DZNE)
Department Research Group for Computational Systems Biology
Lab Bonn-lab
Street address Von-Siebold-Straße 3A
City Göttingen
State/province Niedersachsen
ZIP/Postal code 37075
Country Germany
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (9)
GSM2359030 A30PSORTD8RNA1_rep1
GSM2359031 A30PSORTD8RNA2_rep2
GSM2359032 A30PSORTD8RNA3_rep3
Relations
BioProject PRJNA350311
SRA SRP091992

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Supplementary file Size Download File type/resource
GSE89115_DEG.xls.gz 13.5 Mb (ftp)(http) XLS
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Raw data are available in SRA
Processed data are available on Series record

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