Key Features
Enhance your research with our curated data sets and powerful platform features. Pluto Bio makes it simple to find and use the data you need.
Learn MoreLysosomal 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 2-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 -adrenergic regulation of ClC-7, which can be therapeutically modulated. SOURCE: Sandipkumar Darji (sdarji@nki.rfmh.org) - Nathan Kline Institute for Psychiatric Research
View on GEOView in PlutoEnhance your research with our curated data sets and powerful platform features. Pluto Bio makes it simple to find and use the data you need.
Learn MoreUse Pluto's intuitive interface to analyze and visualize data for this experiment. Pluto's platform is equipped with an API & SDKs, making it easy to integrate into your internal bioinformatics processes.
Read about post-pipeline analysisView quality control data and experiment metadata for this experiment.
Request imports from GEO or TCGA directly within Pluto Bio.
Chat with our Scientific Insights team