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Series GSE89505 Query DataSets for GSE89505
Status Public on Dec 01, 2016
Title Transcriptional profiling of cortex and striatal tissue following chronic dosing of PDE10A inhibitor PF-02545920 in a Q175 homozygous knock-in mouse model of Huntington’s disease
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Huntington’s disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition were required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits.
 
Overall design Transcriptional profiling of cortex and striatal tissue following chronic dosing of either vehicle or the  PDE10A inhibitor PF-02545920 (0.32, 1 and 3.2 mg/kg po qd) in the Q175 homozygous knock-in mouse model of Huntington’s disease (dosing from 5-weeks to 9 months of age).
 
Contributor(s) Aaronson J, Rosinski J
Citation(s) 27916455
Submission date Nov 03, 2016
Last update date May 15, 2019
Contact name Jeff Aaronson
E-mail(s) jeff.aaronson@chdifoundation.org
Phone (609) 945-9616
Organization name CHDI
Department Discovery & Systems Biology
Street address 155 Village Boulevard, Suite 200
City Princeton
State/province New Jersey
ZIP/Postal code 08540
Country USA
 
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (90)
GSM2374861 Hom(Q175) PF-02545920 _0.32mpk Cortex Female rep1
GSM2374862 Hom(Q175) PF-02545920_0.32mpk Cortex Male rep1
GSM2374863 Hom(Q175) PF-02545920_0.32mpk Cortex Female rep2
Relations
BioProject PRJNA352400
SRA SRP092552

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SOFT formatted family file(s) SOFTHelp
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Supplementary file Size Download File type/resource
GSE89505_PDE10a_inhibitor_Counts.xlsx 18.8 Mb (ftp)(http) XLSX
GSE89505_PDE10a_inhibitor_FPKM.xlsx 22.2 Mb (ftp)(http) XLSX
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record
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