A Nucleolar Mechanism Suppresses Organismal Proteostasis by Modulating Signaling of the TGF-β/ERK Axis
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE247737 | GEO | 2024/10/02
REPOSITORIES: GEO
Similar Datasets
Project description:Aberrant protein aggregation jeopardize cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer’s disease (AD) and Huntington’s disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both, the AD-causing Aβ peptide and a stretch of poly-glutamine that is accountable to the development of several disorders including HD, without affecting lifespan. This protection was dependent on the activity of the aging-regulating transcription factors and associated with enhanced Aβ and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modulates the expression of various genes including these which are known as protein homeostasis (proteostasis) regulators such as txt-13, and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.
2023-12-27 | GSE230640 | 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 | 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 | 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 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 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.
2024-09-04 | PXD045561 | Pride
Project description:Krohn2011 - Cerebral amyloid-β
proteostasis regulated by membrane transport protein ABCC1
This model is described in the article:
Cerebral amyloid-β
proteostasis is regulated by the membrane transport protein
ABCC1 in mice.
Krohn M, Lange C, Hofrichter J,
Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T,
Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A,
Gsponer J, Walker LC, Pahnke J.
J. Clin. Invest. 2011 Oct; 121(10):
3924-3931
Abstract:
In Alzheimer disease (AD), the intracerebral accumulation of
amyloid-β (Aβ) peptides is a critical yet poorly understood
process. Aβ clearance via the blood-brain barrier is reduced by
approximately 30% in AD patients, but the underlying mechanisms
remain elusive. ABC transporters have been implicated in the
regulation of Aβ levels in the brain. Using a mouse model of AD
in which the animals were further genetically modified to lack
specific ABC transporters, here we have shown that the
transporter ABCC1 has an important role in cerebral Aβ
clearance and accumulation. Deficiency of ABCC1 substantially
increased cerebral Aβ levels without altering the expression of
most enzymes that would favor the production of Aβ from the Aβ
precursor protein. In contrast, activation of ABCC1 using
thiethylperazine (a drug approved by the FDA to relieve nausea
and vomiting) markedly reduced Aβ load in a mouse model of AD
expressing ABCC1 but not in such mice lacking ABCC1. Thus, by
altering the temporal aggregation profile of Aβ,
pharmacological activation of ABC transporters could impede the
neurodegenerative cascade that culminates in the dementia of
AD.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000618.
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BioModels Database:
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To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000618 | BioModels
Project description:Proteostasis is vital for cellular health, with disruptions leading to pathologies including aging, neurodegeneration and metabolic disorders. Traditionally, proteotoxic stress responses were studied as acute reactions to various noxious factors; however, recent evidence reveals that many stress-response genes exhibit ~12-hour ultradian rhythms under physiological conditions in mammals. These rhythms, driven by an XBP1s-dependent 12h oscillator, are crucial for managing proteostasis. By exploring the chromatin landscape of the murine 12h hepatic oscillator, we identified RBBP5, a key subunit of the COMPASS complex, as an essential epigenetic regulator of proteostasis. RBBP5 is indispensable for regulating both the hepatic 12h oscillator and transcriptional response to acute proteotoxic stress, acting as a co-activator for master proteostasis transcription factor XBP1s. RBBP5 ablation leads to increased sensitivity to proteotoxic stress, chronic inflammation, and hepatic steatosis in mice, along with impaired autophagy and reduced cell survival in vitro. In humans, lower RBBP5 expression is associated with dampened adaptive stress-response gene expression and hepatic steatosis. Our findings establish RBBP5 as a critical regulator of proteostasis, essential for maintaining mammalian organismal health.
2024-10-10 | GSE276159 | GEO
Project description:Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here, we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune cell-specific enhancer signatures as well as immune cell expression quantitative trait loci (eQTL), while decreasing-level enhancer orthologs show fetal brain specific enhancer activity. Surprisingly, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologs implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions. We profiled gene expression levels through RNA-Seq and histone mark levels through ChIP-Seq to compare control mice to the CK-p25 Alzheimer's disease model at 2 weeks and 6 weeks after induction of neurodegeneration.
2015-02-18 | E-GEOD-65159 | biostudies-arrayexpress
Project description:Intron retention (IR) may affect gene expression and protein functions during development and age-onset diseases. However, it remains unclear if IR undergoes spatial or temporal changes during different stages of ageing or neurodegenerative disorders like Alzheimer’s disease (AD). By profiling mRNA species across different ages of Drosophila heads, we observed significant increase in the level of IR of many conserved genes as animals aged. Interestingly, distinct sets of genes are affected at different stages of adult fly life with IR occurring at several AD-associated genes in old adult. This suggests that alteration of proper protein functions by IR during ageing may lead to AD pathogenesis. Consistent with this notion, analyses of healthy human ageing brains and different AD datasets revealed similar increased aberrant IR activities in many AD-curated genes. Taken together, our data suggest that increase IR during ageing may be the driver for late-onset sporadic AD.
2020-02-19 | GSE110349 | GEO
Project description:Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the subproteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for hsc70, the chaperone responsible for substrate targeting to eMI. Age-related hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.
2023-03-11 | PXD035128 | Pride