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β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7

ABSTRACT: β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7

PROVIDER: PRJNA564002 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10070457_1.fastq.gz	Fastqsanger.gz
	SRR10070457_2.fastq.gz	Fastqsanger.gz
	SRR10070458_1.fastq.gz	Fastqsanger.gz
	SRR10070458_2.fastq.gz	Fastqsanger.gz
	SRR10070459_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

β2-adrenergic agonists rescue lysosome acidification and function in PSEN1 deficiency by reversing defective ER to lysosome delivery of ClC-7

Project description: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.

2020-02-29 | GSE136894 | GEO

β2-adrenergic Agonists Rescue Lysosome Acidification and Function in PSEN1 Deficiency by Reversing Defective ER-to-lysosome Delivery of ClC-7.

Project description:Lysosomal dysfunction is considered pathogenic in Alzheimer disease (AD). Loss of presenilin-1 (PSEN1) function causing AD impedes acidification via defective vacuolar ATPase (vATPase) V0a1 subunit delivery to lysosomes. We report that isoproterenol (ISO) and related β2-adrenergic agonists reacidify lysosomes in PSEN1 Knock out (KO) cells and fibroblasts from PSEN1 familial AD patients, which restores lysosomal proteolysis, calcium homeostasis, and normal autophagy flux. We identify a novel rescue mechanism involving Portein Kinase A (PKA)-mediated facilitation of chloride channel-7 (ClC-7) delivery to lysosomes which reverses markedly lowered chloride (Cl-) content in PSEN1 KO lysosomes. Notably, PSEN1 loss of function impedes Endoplasmic Reticulum (ER)-to-lysosome delivery of ClC-7. Transcriptomics of PSEN1-deficient cells reveals strongly downregulated ER-to-lysosome transport pathways and reversibility by ISO, thus accounting for lysosomal Cl- deficits that compound pH elevation due to deficient vATPase and its rescue by β2-adrenergic agonists. Our findings uncover a broadened PSEN1 role in lysosomal ion homeostasis and novel pH modulation of lysosomes through β2-adrenergic regulation of ClC-7, which can potentially be modulated therapeutically.

| S-EPMC7211125 | biostudies-literature

Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration

Project description:Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration

| PRJNA851737 | ENA

Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration [snRNA-Seq]

Project description:Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration [snRNA-Seq]

| PRJNA851741 | ENA

Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration [bulk RNA-Seq]

Project description:Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration [bulk RNA-Seq]

| PRJNA851740 | ENA

Gene expression profile of sporadic and PSEN1 early-onset Alzheimer’s Disease

Project description:Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Around 10% of cases present an age of onset before 65 years-old, which in turn can be divided in monogenic or familial AD (FAD) and sporadic early-onset AD (EOAD). Mutations in PSEN1, PSEN2 and APP genes have been linked with FAD. The aim of our study was to describe the brain whole-genome RNA expression profile of the posterior cingulate area in EOAD and FAD caused by PSEN1 mutations (FAD-PSEN1). 14 patients (7 EOAD and 7 FAD-PSEN1) and 7 neurologically healthy controls were selected and samples were hybridized in a Human Gene 1.1 microarray from Affymetrix. When comparing controls with EOAD and controls with FAD-PSEN1, we found 3183 and 3351 differentially expressed genes (DEG) respectively (FDR corrected p<0.05). However, any DEG was found in the comparison of the two groups of patients. Microarrays were validated through quantitative-PCR of 17 DEG. In silico analysis of the DEG revealed an alteration in biological pathways related to calcium-signaling, axon guidance and long-term potentiation (LTP), among others, in both groups of patients. These pathways are mainly related with cell signalling cascades, synaptic plasticity and learning and memory processes. In conclusion, the altered biological final pathways in EOAD and FAD-PSEN1 are highly coincident. Also, the findings are in line with those previously reported for late-onset AD (LOAD, onset >65 years-old), which implies that the consequences of the disease at the molecular level are similar in the final stages of the disease. 21 Samples were analyzed: 7 controls, 7 Early-onset Alzheimer's disease (AD) patients and 7 early-onset AD genetically determined by a mutation in PSEN1 gene.

2015-01-20 | E-GEOD-39420 | biostudies-arrayexpress

Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice

Project description:PSEN1 ΔE9 mutation causes a familial form of Alzheimer's disease. We have previously shown that human induced pluripotent stem cell (iPSC)-derived astrocytes carrying PSEN1 ΔE9 mutation exhibit transcriptional and functional abnormalities (Stem Cell Reports. 2017;9:1885-1897). Here we injected glial progenitors derived from 2 pairs of PSEN1 ΔE9 mutant- isogenic CTRL iPSCs intracerebroventricularly into newborn mice. At the age of 18 months, mouse hippocampi containing human cells (5 x PSEN1 ΔE9 + 6 x CTRL, all from male mice) were quickly dissected out and bulk RNA sequencing analysis was performed. Our results shed more light on the efffect of PSEN1 ΔE9 mutation on human glia in vivo as well as on the effect of the presence of mutant human glia on the surrounding healthy mouse cells.

2022-12-15 | GSE221027 | GEO

Zebrafish psen1

Project description:Zebrafish - modelling familialAlzheimer's disease using heterozygous K97fs mutation in locus psen1

| PRJEB24858 | ENA

Gene expression profile of sporadic and PSEN1 early-onset Alzheimer’s Disease

2015-01-20 | GSE39420 | GEO

DNA methylation profiles across different brain regions in APP/PSEN1 mice

Project description:Genome wide DNA methylation profiling of normal and APP/PSEN1 mice. A custom Illumina Golden Gate DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 800 CpGs. Bisulphite converted DNA from the 96 samples were hybridised to the Illumina custom golden gate DNA methylation array.

2015-12-05 | E-GEOD-42745 | biostudies-arrayexpress

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