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| Status |
Public on May 30, 2019 |
| Title |
Lysosomal dysfunction in Down syndrome is APP-dependent and mediated by APP-βCTF (C99) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Third-party reanalysis
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| Summary |
Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer’s disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down Syndrome (Trisomy 21) requires the extra gene copy of amyloid precursor protein (APP) and is mediated by the beta cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with Down Syndrome (DS), lysosomal degradation of autophagic and endocytic substrates is selectively impaired causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) associated with slowed LC3 turnover and the inactivation of cathepsin D (CTSD) and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, implicating pH elevation as their primary basis. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one BACE1 allele from adult Ts2 mice had similar rescue effects in vivo. The modest elevation of endogenous APP-βCTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-βCTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD.
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| Overall design |
(1) mRNA-Seq profiling of six Trisomic and six Disomic human fibroblasts samples (3 replicates from 2 individuals in each group) from 5 months (3 replicates) and 2 years (3 replicates) old unrelated inviduals treated with either siRNA against human APP (siAPP) or a negative control DsiRNA (siNC). (2) A separate Differential Gene Expression (DGE) analysis was also carried out to compare transcriptomic profile of human Disomic and Trisomic fibroblasts using Disomic samples treated with siNC (3 replicates each of 5 months and 2 years individuals; Total = 6) in conjunction with age matched untreated human Disomic fibroblasts samples already deposited by Letourneau et al. (GSM1338333, GSM1338336) and Sullivan et al. (GSM2105075, GSM2105077); and Trisomic samples treated with siNC (3 replicates each of 5 months and 2 years individuals; Total = 6) in conjunction with age matched untreated human Trisomic fibroblasts samples from Letourneau et al. (GSM1338325, GSM1338326, GSM1338327) and Sullivan et al. (GSM2105044, GSM2105047). The final count of samples for the Disomic and Trisomic group is 11 and 10 respectively.
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| Contributor(s) |
Jiang Y, Sato Y, Im E, Berg M, Bordi M, Darji S, Kumar A, Mohan PS, Bandyopadhyay U, Diaz A, Cuervo AM, Nixon RA |
| Citation(s) |
31043483 |
| Submission date |
Mar 05, 2019 |
| Last update date |
Jun 05, 2019 |
| Contact name |
Sandipkumar Darji |
| E-mail(s) |
sdarji@nki.rfmh.org
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| Organization name |
Nathan Kline Institute for Psychiatric Research
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| Department |
Center for Dementia Research
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| Street address |
140 Old Orangeburg Rd, Bldg 39
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| City |
Orangeburg |
| State/province |
NY |
| ZIP/Postal code |
10962 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (24)
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| GSM3640444 |
Trisomic, -ve control DsiRNA treated, 5 months, replicate 1 |
| GSM3640445 |
Trisomic, -ve control DsiRNA treated, 5 months, replicate 2 |
| GSM3640446 |
Trisomic, -ve control DsiRNA treated, 5 months, replicate 3 |
| GSM3640447 |
Trisomic, -ve control DsiRNA treated, 2 years, replicate 1 |
| GSM3640448 |
Trisomic, -ve control DsiRNA treated, 2 years, replicate 2 |
| GSM3640449 |
Trisomic, -ve control DsiRNA treated, 2 years, replicate 3 |
| GSM3640450 |
Disomic, -ve control DsiRNA treated, 5 months, replicate 1 |
| GSM3640451 |
Disomic, -ve control DsiRNA treated, 5 months, replicate 2 |
| GSM3640452 |
Disomic, -ve control DsiRNA treated, 5 months, replicate 3 |
| GSM3640453 |
Disomic, -ve control DsiRNA treated, 2 years, replicate 1 |
| GSM3640454 |
Disomic, -ve control DsiRNA treated, 2 years, replicate 2 |
| GSM3640455 |
Disomic, -ve control DsiRNA treated, 2 years, replicate 3 |
| GSM3640456 |
Trisomic, siAPP treated, 5 months, replicate 1 |
| GSM3640457 |
Trisomic, siAPP treated, 5 months, replicate 2 |
| GSM3640458 |
Trisomic, siAPP treated, 5 months, replicate 3 |
| GSM3640459 |
Trisomic, siAPP treated, 2 years, replicate 1 |
| GSM3640460 |
Trisomic, siAPP treated, 2 years, replicate 2 |
| GSM3640461 |
Trisomic, siAPP treated, 2 years, replicate 3 |
| GSM3640462 |
Disomic, siAPP treated, 5 months, replicate 1 |
| GSM3640463 |
Disomic, siAPP treated, 5 months, replicate 2 |
| GSM3640464 |
Disomic, siAPP treated, 5 months, replicate 3 |
| GSM3640465 |
Disomic, siAPP treated, 2 years, replicate 1 |
| GSM3640466 |
Disomic, siAPP treated, 2 years, replicate 2 |
| GSM3640467 |
Disomic, siAPP treated, 2 years, replicate 3 |
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| Relations |
| Reanalysis of |
GSM1338333 |
| Reanalysis of |
GSM1338336 |
| Reanalysis of |
GSM2105075 |
| Reanalysis of |
GSM2105077 |
| Reanalysis of |
GSM1338325 |
| Reanalysis of |
GSM1338326 |
| Reanalysis of |
GSM1338327 |
| Reanalysis of |
GSM2105044 |
| Reanalysis of |
GSM2105047 |
| BioProject |
PRJNA525687 |
| SRA |
SRP187586 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE127880_TMM_normalized_CountsPerMillion.txt.gz |
654.7 Kb |
(ftp)(http) |
TXT |
| GSE127880_TMM_normalized_CountsPerMillion_siRNA_treatment.txt.gz |
799.3 Kb |
(ftp)(http) |
TXT |
| GSE127880_TMM_normalized_TPMCounts.txt.gz |
3.1 Mb |
(ftp)(http) |
TXT |
| GSE127880_TMM_normalized_TPMCounts_siRNA_treatment.txt.gz |
5.4 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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