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Series GSE136894 Query DataSets for GSE136894
Status Public on Feb 29, 2020
Title β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Lysosomal dysfunction is considered pathogenic in Alzheimer Disease (AD). Loss of Presenilin-1(PSEN1) function causing early onset AD impedes acidification via defective vATPase V0a1 subunit delivery to lysosomes. We report that isoproterenol and related β2-adrenergic agonists re-acidify lysosomes in PSEN1 KO cells and fibroblasts from PSEN1 familial AD(FAD) patients, restores lysosomal calcium homeostasis and proteolysis, and reverses impaired autophagy flux. We identify a novel rescue mechanism involving PKA-mediated facilitated delivery of ClC-7 to lysosomes, which stimulates chloride influx and reverses markedly lowered Cl- content of PSEN1 KO lysosomes. Notably, PSEN1 loss-of-function impedes ER-to-lysosome delivery of ClC-7, thus accounting for lysosomal Cl- deficits that compound pH deficits due to deficient vATPase function. Transcriptomics of PSEN1-deficient cells reveal strongly down-regulated ER-to-lysosome transport pathways and reversibility by isoproterenol. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through β-adrenergic regulation of ClC-7, which can be therapeutically modulated.
 
Overall design mRNA-seq profiling of PSEN1 KO and WT murine blastocysts (BD) cells with and without Isoproterenol (ISO) treatment; 3 biological replicates from each group.
 
Contributor(s) Lee J, Wolfe DM, Darji S, McBrayer M, Colacurcio DJ, Kumar A, Stavrides P, Mohan PS, Nixon RA
Citation(s) 32105735
Submission date Sep 05, 2019
Last update date May 30, 2020
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)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (12)
GSM4061295 PSEN1 KO, replicate 1
GSM4061296 PSEN1 KO, replicate 2
GSM4061297 PSEN1 KO, replicate 3
Relations
BioProject PRJNA564002
SRA SRP220423

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Supplementary file Size Download File type/resource
GSE136894_countsPerMillion_filt_TMMnorm.txt.gz 1.3 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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