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| Status |
Public on Apr 21, 2020 |
| Title |
Truncation of mutant huntingtin in knock-in mice via CRISPR-Cas9 uncovers exon1 huntingtin as a key pathogenic form |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
It remains unknown how polyglutamine expansion in widely expressed proteins can cause selective neurodegeneration. In Huntington’s disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Considerable efforts have been devoted to investigating how HTT is cleaved and whether blocking its cleavage is therapeutically beneficial. However, using CRISPR-Cas9 to truncate full-length mutant Htt in HD140Q knock-in (KI) mice, we found that exon1 Htt is stably present in the brain, regardless of truncation sites in full-length Htt. This N-terminal Htt led to similar HD phenotypes and age-dependent Htt accumulation in striatum in different KI mice. Exon1 Htt is constantly generated but its selective accumulation in the striatum is caused by the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function accounts for the selective neuropathology in HD and highlight therapeutic importance in regulating this function.
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| Overall design |
We performed RNAseq analysis using striatal tissues from WT, KI-96, KI-571 and KI-FL mice, which are different lines of HD KI mice.
KI-FL expresses full-length mutant Huntingtin, KI-571 expresses an N-terminal Huntingtin fragment, KI-96 expresses an N-terminal Huntingtin fragment shorter than KI-571.
Please note that the processed data columns T1_1 to T1_4 (in the processed_count_matrix.txt) should be disregarded.
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| Contributor(s) |
Yang S, Li X |
| Citation(s) |
32444599 |
| |
| Submission date |
Feb 25, 2020 |
| Last update date |
Jun 08, 2020 |
| Contact name |
Su Yang |
| Organization name |
Jinan University
|
| Street address |
Huangpu Avenue
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| City |
Guangzhou |
| ZIP/Postal code |
510000 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (19)
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| Relations |
| BioProject |
PRJNA608647 |
| SRA |
SRP250656 |
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