Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA974377 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24658168.fastq.gz | Fastqsanger.gz | |||
| SRR24658169.fastq.gz | Fastqsanger.gz | |||
| SRR24658170.fastq.gz | Fastqsanger.gz | |||
| SRR24658171.fastq.gz | Fastqsanger.gz | |||
| SRR24658172.fastq.gz | Fastqsanger.gz |
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Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ), is controversial. Using an activity based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.
2024-09-03 | GSE232889 | GEO
Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.
2024-09-03 | PXD045565 | Pride
Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.
2024-09-03 | PXD045531 | Pride
Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the ADcausing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ– mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.
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Project description:Tumor-associated macrophages (TAMs) have emerged as prominent cells within the tumor microenvironment playing critical roles in extracellular matrix remodeling, tumor cell proliferation and invasion, angiogenesis, and metastasis. Cathepsin proteases, produced by tumor cells and TAMs, have been demonstrated to mediate these processes, but it still remains unclear how these typically lysosomal enzymes are capable of executing their functions in the extracellular space. Here we identify a novel interaction between STAT6 and STAT3 that potently upregulates cathepsin secretion in macrophages in response to TH2 cytokine stimulation. Systematic gene expression analyses reveal that the TH2 cytokine IL-4 synergizes with IL-6 or IL-10 to activate the IRE1α/ XBP1 axis of the unfolded protein response. Pharmacological inhibition of the IRE1α axis blunts cathepsin secretion in macrophages and blocks macrophage-mediated tumor cell invasion. Finally, we show that genetic ablation of either STAT6 or STAT3 signaling impairs tumor development and invasion. Thus, these findings demonstrate that TH2 cytokine-mediated STAT6 and STAT3 activation in macrophages promotes a professional secretory phenotype capable of enhancing tumor cell invasion in a cathepsin-dependent manner.
2016-08-17 | GSE70626 | GEO
Project description:The protein homeostasis (proteostasis) network encompasses a myriad of mechanisms that maintain the integrity of the proteome by controlling various biological functions, including protein folding and degradation. Alas, aging-associated decline in the efficiency of this network enables protein aggregation and consequently the development of late onset neurodegenerative disorders, such as Alzheimer’s disease (AD). Accordingly, the maintenance of proteostasis through late stages of life bears the promise to delay the emergence of these devastating diseases. Yet, the identification of proteostasis-regulators is needed to assess the feasibility of this approach. Here we report that knocking down the activity of the nucleolar FIB-1-NOL-56 complex, protects model nematodes from proteotoxicity of the AD-causing, Aβ peptide. This mechanism promotes proteostasis across tissues by modulating the activity of TGF-β signaling and by enhancing proteasome activity. Our findings point at new research avenues toward the development of proteostasis-promoting therapies for neurodegenerative maladies.
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Project description:Microglia, the innate immune cells of the central nervous system, perform critical inflammatory and non-inflammatory functions to maintain homeostasis and normal neural function. However in Alzheimer’s disease (AD), these beneficial functions become progressively impaired, contributing to synapse and neuron loss and cognitive impairment. The inflammatory cyclooxygenase-PGE2 pathway, including the PGE2 receptor EP2, is implicated in AD development, both in human epidemiology and in transgenic models of AD. To test the transcriptional responses of EP2-deficient microglia to Aβ in vivo, we used mice in which the EP2 receptor is conditionally deleted in microglia using the CD11b-Cre transgene and floxed alleles of the EP2 gene. By injecting these mice with Aβ ICV and isolating microglia from the brains, we have been able to establish the transcriptional response of microglia to Aβ in vivo and test how EP2 deletion in microglia affects this response. 8 month-old C57BL/6 mice, of the genotype CD11b-Cre; EP2+/+ or CD11b-Cre; EP2lox/lox, were injected I.C.V. with either Aβ or vehicle. 48 hours after injection, the mice were sacrificed and transcardially perfused with cold heparinized 0.9% NaCl. Brains were then removed from the mice and pooled, two brains of the same genotype per sample, to ensure adequate cell and RNA yield. The brains were then enzymatically dissociated for microglia isolation using the Neural Tissue Dissociation Kit (P), MACS Separation Columns (LS), and magnetic CD11b Microbeads from Miltenyi Biotec according to the manufacturer's protocol. Immediately after isolating the microglia, RNA was extracted from the cells for microarray analysis.
2015-02-20 | E-GEOD-57181 | biostudies-arrayexpress
Project description:Cathepsin L is a lysosomal protease that is secreted by several cancer cells. Cathepsin L upregulation has been widely associated with poor clinical outcome and increased metastatic incidence. However, whether Cathepsin L participates in tumor angiogenesis remains less studied. Our study showed a significant activation of angiogenic capacity of endothelial cells in presence of purified or tumor derived Cathepsin L. In addition, Cathepsin L exposure led to a significant increase in the proliferative capacity of endothelial cells. While the ability of Cathepsin L to promote endothelial cell sprouting, migration, invasion and tube formation can be attributed to its proteolytic effects on extracellular matrix, how it promotes endothelial cell proliferation remains obscure. The objective of this study was to test if Cathepsin L exposure can activate signaling cascades and gene expression leading to proliferation of endothelial cells.
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Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.
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