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| Status |
Public on Sep 29, 2008 |
| Title |
Nrf2-related oxidative stress response and impaired dopamine biosynthesis in a PC12 cell model of Huntington’s disease |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
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| Summary |
Huntington’s disease (HD) is a devastating disease for which currently no therapy is available. It is a progressive autosomal dominant neurodegenerative disorder that is caused by a CAG repeat expansion in the HD gene, resulting in an expansion of polyglutamines at the N-terminal end of the encoded protein, designated huntingtin, and the accumulation of cytoplasmic and nuclear aggregates. Not only is there a loss of normal huntingtin function, upon expansion of the CAG repeat there is also a gain of toxic function of the huntingtin protein and this affects a wide range of cellular processes. To identify groups of genes that could play a role in the pathology of Huntington’s disease, we studied mRNA changes in an inducible PC12 model of Huntington’s disease before and after aggregates became visible. This is the first study to show the involvement Nrf2-responsive genes in the oxidative stress response in HD. Oxidative stress related transcripts were altered in expression suggesting a protective response in cells expressing mutant huntingtin at an early stage of cellular pathology. Furthermore, there was a down-regulation of catecholamine biosynthesis resulting in lower dopamine levels in culture. Our results further demonstrate an early impairment of transcription, the cytoskeleton, ion channels and receptors. Given the pathogenic impact of oxidative stress and neuroinflammation, the Nrf2-ARE signaling pathway is an attractive therapeutic target for neurodegenerative diseases.
Keywords: Gene expression analysis, Huntington's disease, oxidative stress, PC12 cell model
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| Overall design |
For each construct, we performed duplicate experiments with 2 independent cell lines for each construct yielding 2 biological replicates. Furthermore, from each cell line, two separate RNA isolations were performed serving as technical replicates. For PC12 cells with no construct, only a technical replicate was used. RNA was harvested prior to induction (day 0), after 24 hours of induction (day 1) and after 5 days of induction of exon 1 huntingtin fragments with normal (Q23) and extended (Q74) glutamine repeat length.
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| Contributor(s) |
van Roon-Mom WW, Pepers BA, 't Hoen PA, Verwijmeren CA, den Dunnen JT, Dorsman JC, van Ommen GB |
| Citation(s) |
18844975 |
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| Submission date |
Feb 20, 2008 |
| Last update date |
Jul 29, 2014 |
| Contact name |
Peter A.C. 't Hoen |
| E-mail(s) |
p.a.c.hoen@lumc.nl
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| Phone |
+31 71 5269421
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| Fax |
+31 71 5268285
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| URL |
http://www.humgen.nl
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| Organization name |
Leiden University Medical Center
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| Department |
Center for Human and Clinical Genetics
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| Street address |
PO Box 9600
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| City |
Leiden |
| ZIP/Postal code |
2300 RC |
| Country |
Netherlands |
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| Platforms (1) |
| GPL6101 |
Illumina ratRef-12 v1.0 expression beadchip |
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| Samples (30)
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| GSM266857 |
Construct Q23 Line 1 0 days (Q23_0_1_1) |
| GSM266858 |
Construct Q23 Line 1 1 days (Q23_1_1_1) |
| GSM266859 |
Construct Q23 Line 1 5 days (Q23_5_1_1) |
| GSM266860 |
Construct Q74 Line 4 0 days (Q74_0_4_1) |
| GSM266861 |
Construct Q74 Line 4 1 days (Q74_1_4_1) |
| GSM266862 |
Construct Q74 Line 4 5 days (Q74_5_4_1) |
| GSM266863 |
Construct Q23 Line 5 0 days (Q23_0_5_1) |
| GSM266864 |
Construct Q23 Line 5 1 days (Q23_1_5_1) |
| GSM266865 |
Construct Q23 Line 5 5 days (Q23_5_5_1) |
| GSM266866 |
Construct Q74 Line 6 0 days (Q74_0_6_1) |
| GSM266867 |
Construct Q74 Line 6 1 days (Q74_1_6_1) |
| GSM266868 |
Construct Q74 Line 6 5 days (Q74_5_6_1) |
| GSM266869 |
Construct Q23 Line 1 0 days (Q23_0_1_2) |
| GSM266870 |
Construct Q23 Line 1 1 days (Q23_1_1_2) |
| GSM266871 |
Construct Q23 Line 1 5 days (Q23_5_1_2) |
| GSM266872 |
Construct Q74 Line 4 0 days (Q74_0_4_2) |
| GSM266873 |
Construct Q74 Line 4 1 days (Q74_1_4_2) |
| GSM266874 |
Construct Q74 Line 4 5 days (Q74_5_4_2) |
| GSM266875 |
Construct Q23 Line 5 0 days (Q23_0_5_2) |
| GSM266876 |
Construct Q23 Line 5 1 days (Q23_1_5_2) |
| GSM266877 |
Construct Q23 Line 5 5 days (Q23_5_5_2) |
| GSM266878 |
Construct Q74 Line 6 0 days (Q74_0_6_2) |
| GSM266879 |
Construct Q74 Line 6 1 days (Q74_1_6_2) |
| GSM266880 |
Construct Q74 Line 6 5 days (Q74_5_6_2) |
| GSM266881 |
Empty PC12 0 days (PC12_0_1_1) |
| GSM266882 |
Empty PC12 1 days (PC12_1_1_1) |
| GSM266883 |
Empty PC12 5 days (PC12_5_1_1) |
| GSM266884 |
Empty PC12 0 days (PC12_0_2_2) |
| GSM266885 |
Empty PC12 1 days (PC12_1_2_2) |
| GSM266886 |
Empty PC12 5 days (PC12_5_2_2) |
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| Relations |
| BioProject |
PRJNA107845 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE10581_RAW.tar |
2.8 Mb |
(http)(custom) |
TAR |
| GSE10581_raw.txt |
31.1 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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