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

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

PROVIDER: PRJNA851741 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19782421.fastq.gz	Fastqsanger.gz
	SRR19782422.fastq.gz	Fastqsanger.gz
	SRR19782423.fastq.gz	Fastqsanger.gz
	SRR19782424.fastq.gz	Fastqsanger.gz
	SRR19782425.fastq.gz	Fastqsanger.gz

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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 [bulk RNA-Seq]

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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-30 | GSE206666 | GEO

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

Project description:We report the application of snRNA-seq in the mouse cortex with C9FTD/ALS neurodegeneration

2023-06-30 | GSE206664 | GEO

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

Project description:We report the application of buld RNA-seq in the mouse cortex with C9FTD/ALS neurodegeneration

2023-06-30 | GSE206665 | GEO

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

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

| PRJNA564002 | ENA

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

Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

Project description:Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

2023-06-24 | GSE235312 | GEO

RNA-Seq Samples of siTFE3 in 8988T PDA Cell Line to Investigate Transcriptional Control of the Autophagy-Lysosome System

Project description:The activation of cellular quality control pathways to maintain metabolic homeostasis and mitigate diverse cellular stresses is emerging as a critical growth and survival mechanism in many cancers. Autophagy, a highly conserved cellular self-degradative process, is a key player in the initiation and maintenance of pancreatic ductal adenocarcinoma (PDA). However, the regulatory circuits that activate autophagy, and how they enable reprogramming of PDA cell metabolism are unknown. We now show that autophagy regulation in PDA occurs as part of a broader program that coordinates activation of lysosome biogenesis, function and nutrient scavenging, through constitutive activation of the MiT/TFE family of bHLH transcription factors. In PDA cells, the MiT/TFE proteins - MITF, TFE3 and TFEB - override a regulatory mechanism that controls their nuclear translocation, resulting in their constitutive activation. By orchestrating the expression of a coherent network of genes that induce high levels of lysosomal catabolic function, the MiT/TFE factors are required for proliferation and tumorigenicity of PDA cells. Importantly, unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosomal activation is specifically required to maintain intracellular AA pools in PDA. This AA flux is part of a program that is essential for metabolic homeostasis and bioenergetics of PDA but not for their non-transformed counterparts. These results identify the MiT/TFE transcription factors as master regulators of the autophagy-lysosomal system in PDA and demonstrate a central role of the autophagosome-lysosome compartment in maintaining tumor cell metabolism through alternative amino acid acquisition and utilization. Examination of mRNA levels in pancreatic ductal adenocarcinoma (PDA) cell line 8988T after treatment with siRNA for control or TFE3

2015-04-03 | E-GEOD-62077 | biostudies-arrayexpress

Quantitative Phosphoproteomic Analyses Identify STK11IP as a Lysosome-Specific Substrate of mTORC1 that Regulates Lysosomal Acidification

Project description:The evolutionarily conserved serine/threonine kinase mTORC1 is a central regulator of cell growth and proliferation. mTORC1 is activated on the lysosome surface. However, once mTORC1 is activated, it is unclear whether mTORC1 phosphorylates local lysosomal proteins to regulate specific aspects of lysosomal biology. By integrating analyses of lysosome proteome with mTORC1-regulated phosphoproteome, we identify STK11IP as a lysosome-specific substrate of mTORC1. mTORC1 phosphorylates STK11IP at S404. Knockout of STK11IP leads to a robust increase of autophagy flux. Dephosphorylation of STK11IP at S404 represses the role of STK11IP as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase, and regulates the activity of V-ATPase. Knockout of STK11IP protects mice from fasting or Methionine/Choline-Deficient Diet diet-induced fatty liver. Thus, our study demonstrates that STK11IP phosphorylation represents a novel mechanism for mTORC1 to regulate lysosomal acidification and autophagy, and points to STK11IP as a promising therapeutic target for the amelioration of diseases with aberrant autophagy signaling.

2022-05-20 | PXD031543 | Pride

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