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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 20, 2023 |
| Title |
Selected Spt5-Pol II inhibitors effectively relieve Huntington’s disease neuropathology and slow down its progression in mice [INCPMPM-17698] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Huntington’s disease (HD) is an incurable inherited disorder caused by repeat expansion in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological abnormalities. Selective downregulation of the mutant Htt by targeting Spt4/Spt5 or the Spt5-PolII transcription elongation complexes was proposed as a potential therapy. We report the identification of SPI-24 and SPI-77 small molecule inhibitors of Spt5-PolII that selectively lower mutant Htt. In the BACHD mouse model of HD, direct delivery to the striatum, subcutaneous injection and oral administration of these inhibitors diminished mutant Htt levels, ameliorated mitochondrial dysfunction and restored BDNF expression. Prolonged treatment attenuated motor and anxious-like phenotypes of HD mice and delayed disease deterioration. SPI-24 long-term treatment had no side-effects or global changes in gene expression. Mechanistically, SPIs reduce Spt5 and PolII occupancies of mutant Htt. Thus, SPIs can be an effective therapeutic strategy for HD.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for brain cells derived from BACHD mice treated for long term with either DMSO or SPI-24
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| Contributor(s) |
Bahat A, Itzhaki E, Weiss B, Tolmasov M, Tsoory M, Kuperman Y, Brandis A, Shurrush KA, Dikstein R |
| Citation(s) |
38374466 |
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| Submission date |
Feb 22, 2023 |
| Last update date |
Mar 20, 2024 |
| Contact name |
Rivka Dikstein |
| E-mail(s) |
rivka.dikstein@weizmann.ac.il
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| Organization name |
Weizmann Institute of Science
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| Department |
Biomolecular Sciences
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| Street address |
234 Herzel
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| City |
Rehovot |
| ZIP/Postal code |
7610001 |
| Country |
Israel |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (10)
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| GSM7056308 |
BACHD, DMSO, 8 weeks. bio rep4 |
| GSM7056309 |
BACHD, DMSO, 8 weeks. bio rep5 |
| GSM7056310 |
BACHD, SPI-24, 8 weeks, bio rep1 |
| GSM7056311 |
BACHD, SPI-24, 8 weeks, bio rep2 |
| GSM7056312 |
BACHD, SPI-24, 8 weeks, bio rep3 |
| GSM7056313 |
BACHD, SPI-24, 8 weeks, bio rep4 |
| GSM7056314 |
BACHD, SPI-24, 8 weeks, bio rep5 |
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| This SubSeries is part of SuperSeries: |
| GSE225790 |
Selected Spt5-Pol II inhibitors effectively relieve Huntington’s disease neuropathology and slow down its progression in mice |
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| Relations |
| BioProject |
PRJNA937617 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE225789_processed.xlsx |
2.5 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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