 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Jun 22, 2019 |
| Title |
mTOR hyperactivation in Down Syndrome mediates deficits in autophagy induction, autophagosome formation, and mitophagy |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.
|
| |
|
| Overall design |
mRNA-Seq profiling of 9 2N and 8 DS human fibroblasts samples of age 5 months (< 1 year) and 2 years. These samples come from 5 unrelated 2N individuals (of which 2 individuals, one each of 5 months and 2 years, have 3 replicates each) and 3 unrelated DS individuals (of which 2 individuals, one each of 5 months and 2 years, have 3 replicates each). Five samples were reanalyzed from GSE55504.
|
| |
|
| Contributor(s) |
Bordi M, Darji S, Sato Y, Mellén M, Berg MJ, Kumar A, Jiang Y, Nixon RA |
| Citation(s) |
31332166 |
| Submission date |
Feb 21, 2019 |
| Last update date |
Jul 25, 2019 |
| Contact name |
Sandipkumar Darji |
| E-mail(s) |
sdarji@nki.rfmh.org
|
| Organization name |
Nathan Kline Institute for Psychiatric Research
|
| Department |
Center for Dementia Research
|
| Street address |
140 Old Orangeburg Rd, Bldg 39
|
| City |
Orangeburg |
| State/province |
NY |
| ZIP/Postal code |
10962 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
|
| Samples (12)
|
|
| Relations |
| Reanalysis of |
GSM1338325 |
| Reanalysis of |
GSM1338326 |
| Reanalysis of |
GSM1338327 |
| Reanalysis of |
GSM1338333 |
| Reanalysis of |
GSM1338336 |
| BioProject |
PRJNA523635 |
| SRA |
SRP186520 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE126910_TMM_normalized_ReadCounts.txt.gz |
512.5 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...