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Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Caenorhabditis Elegans

TISSUE(S): Whole Body

SUBMITTER: Atif Ahmed

LAB HEAD: Ehud Cohen

PROVIDER: PXD045531 | Pride | 2024-09-03

REPOSITORIES: Pride

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			Action	DRS
	20220511-07-A1.raw	Raw
	20220511-09-A2.raw	Raw
	20220511-11-A3.raw	Raw
	20220511-13-A4.raw	Raw
	20220511-16-A5.raw	Raw

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Similar Datasets

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

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

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

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

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

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

Effects of intracellular amyloid toxicity on the transcriptome of MC65 human nerve cells

Project description:Amyloid beta (Aβ) accumulates within neurons in the brains of early stage Alzheimer's disease (AD) patients. However, the mechanism underlying its potential toxicity remains unclear. To elucidate this, a transcriptomic study was carried out using a nerve cell model of toxic intracellular aggregation of Aβ. The neuroprotective compound CMS121 was included as a validating tool. It was found that intracellular Aβ induces profound changes in the omics landscape of nerve cells that are associated with a cancer-like metabolic reprogramming, the oxytosis/ferroptosis cell death program, and physiological alterations detrimental to mitochondrial function. Our findings have implications for the understanding of the basic biology of proteotoxicity, aging and AD as well as for the development of future therapeutic interventions designed to target the oxytosis/ferroptosis programmed cell death pathway in the AD brain.

2020-10-22 | GSE144194 | GEO

A Short Peptide Protects from Age-Onset Proteotoxicity

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

GM1 promotes early Aβ oligomer formation and maintenance

Project description:The aggregation of amyloid beta (Aβ) peptide is associated with Alzheimer’s disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aβ fibrils, yet little is known about the roles of GM1 in the early steps of Aβ oligomer formation. Here, by using GM1-contained liposomes as a mimic of neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aβ oligomerization and aggregation. We find that GM1 not only promotes the formation of Aβ fibrils, but also facilitates the maintenance of Aβ oligomers on liposome membranes. We structurally characterize the Aβ oligomers formed on the membrane and find that GM1 captures Aβ by binding to its arginine-5 residue. To interrogate the mechanism of Aβ oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the Aβ ion channel hypothesis. Finally, we conduct cell viability assay to determine the toxicity of Aβ oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early Aβ oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.

2023-05-10 | PXD029117 | Pride

The structural mechanism of MCIA complex assembly links mitochondrial redox pathways

Project description:The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer’s disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.

2023-12-13 | PXD042858 | Pride

Expression data from Saccharomyces cerevisiae

Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Oligomers of Amyloid-β peptides (Aβ) are thought to play a pivotal role in AD pathogenesis, yet the mechanisms involved remain unclear. Two major isoforms of Aβ associated with AD are Aβ40 and Aβ42, the latter being more prone to form oligomers and toxic. Humanized yeast models are currently applied to unravel the cellular mechanisms behind Aβ toxicity. Here, we took a systems biology approach to study two yeast AD models which expressed either Aβ40 or Aβ42 in bioreactor cultures. Strict control of oxygen availability and culture pH, strongly affected the chronological lifespan and reduced confounding effects of variations during cell growth. Reduced growth rates and biomass yields were observed upon expression of Aβ42, indicating a redirection of energy from growth to maintenance. Quantitative physiology analyses furthermore revealed reduced mitochondrial functionality and ATP generation in Aβ42 expressing cells, which matched with observed aberrant fragmented mitochondrial structures. Genome-wide expression levels analysis showed that Aβ42 expression triggers strong ER stress and unfolded protein responses (UPR). Expression of Aβ40 induced only mild ER stress, leading to activation of UPR target genes that cope with misfolded proteins, which resulted in hardly affected physiology. The combination of well-controlled cultures and AD yeast models strengthen our understanding of how cells translate different levels of Aβ toxicity signals into particular cell fate programs, and further enhance their role as a discovery platform to identify potential therapies.

2017-08-31 | GSE94793 | GEO

The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination

2023-12-13 | PXD042905 | Pride

Proteomic analysis of the entorhinal cortex and CA1 subfields of the hippocampus of macaques injected with tau seeds from Alzheimer’s brain

Project description:The "prion-like" features of Alzheimer’s disease (AD) tauopathy and its relationship with amyloid β (Aβ) has never been experimentally studied in primates phylogenetically close to humans. We injected 17 macaques in the entorhinal cortex with nanograms of tau proteopathic seeds purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of recombinant Aβ oligomers. After neuropathological examination of the macaque’s brain, we also performed mass spectrometry-based proteomics of macaques’ entorhinal cortex and CA1 to study the spatial response (local and distant) to tau seeds injections (and its modulation by oligomeric Aβ).

2024-01-02 | PXD040522 | Pride

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