Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mitochondria serve as a Holdout Compartment for Aggregation-Prone Proteins hindering Efficient Degradation

ABSTRACT: The accumulation of protein aggregates has been causatively linked to the pathogenesis of neurodegenerative diseases. Here, we have conducted a genome-wide CRISPR-Cas9 screen to identify cellular factors that regulate the degradation of an aggregation-prone reporter protein. We found that genes encoding proteins involved in mitochondrial homeostasis, including the translation factor eIF5A, were enriched among suppressors of the degradation of the reporter. Genetic or chemical inhibition of eIF5A led to dissociation of the aggregation-prone substrate from mitochondria, which was accompanied by enhanced ubiquitination at the endoplasmic reticulum. The presence of an aggregation-prone, amphipathic helix that localized the reporter to mitochondria was crucial for the stimulatory effect of eIF5A inhibition on proteasomal degradation. Additionally, inhibition of eIF5A also enhanced degradation of mutant huntingtin and α-synuclein, two disease-associated proteins that contain amphipathic helices and mislocalize to mitochondria. We propose thatmitochondria serve as a holdout compartment for aggregation-prone proteins, keeping them out of reach of ubiquitination enzymes that target them for degradation. Therefore, preventing mitochondrial localization of aggregation-prone proteins may offer a viable therapeutic strategy for reducing disease-associated proteins in neurodegenerative disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328470 | GEO | 2026/05/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of generic impact of protein aggregation (aggregation of proteins not associated with neurodegenerative disease) on gene expression in human cultured cells

Project description:In this study the generic impact of protein aggregation (aggregation of proteins not associated with neurodegenerative disease) on gene expression in cultured cells was investigated by DNA microarray technology. The survey of gene expression showed that the Hsp40, Hsp70 and Hsp105 genes, all of which have documented aggregation suppression activity, were up-regulated. Unexpectedly, the survey also showed increased expression of the MEK5 gene with concomitant silencing of the MEK3 gene. The expression pattern of MEK5 at the mRNA and protein levels aligns with the kinetics of aggregate formation and dissolution. Cell viability was unaffected by protein aggregates. These findings are of particular importance for chronic neurodegenerative diseases where the intraneuronal accumulation of aggregate-prone proteins are a major characteristic of the diseases. The identification of changes in MEK5 gene expression have been observed in Alzheimer-related diseases which provides new diagnostic and therapeutic avenues in these diseases. The molecular neuropathological findings would not have occurred without the generic microarray analyses.

2005-07-20 | E-MEXP-389 | biostudies-arrayexpress

Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington’s Disease

Project description:Huntington’s disease (HD) is a neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene, encoding a homopolymeric polyglutamine (polyQ) tract. Although mutant HTT (mHTT) protein is known to aggregate, the links between aggregation and neurotoxicity remain unclear. Here we show that both translation and aggregation of wild-type and mHTT are regulated by a stress-responsive upstream open reading frame, and that polyQ expansions cause abortive translation termination and release of truncated, aggregation-prone mHTT fragments. Notably, we find that mHTT depletes translation elongation factor eIF5A in brains of symptomatic HD mice and cultured HD cells, leading to pervasive ribosome pausing and collisions. Loss of eIF5A disrupts homeostatic controls and impairs recovery from acute stress. Importantly, drugs that inhibit translation initiation reduce premature termination and mitigate this escalating cascade of ribotoxic stress and dysfunction in HD.

2024-03-13 | PXD026012 | Pride

BAG2 Condensates Couple Proteostasis to CD8 + T Cell Surveillance

Project description:Protein aggregation, impaired degradation, and immune activation are central hallmarks of many neurodegenerative diseases, yet how these processes are coordinated remain unclear. Here we identify a new class of phase-separated proteostasis organelles, termed immune degradation condensates (IDCs), composed of BAG2 assemblies. Inflammatory cues drive the formation of BAG2 IDCs, which are enriched in immunoproteasome components, major histocompatibility complex class I (MHC-I) peptide-loading machinery, and chaperones associated with the endoplasmic reticulum (ER). These assemblies redirect proteostatic cargo from centrosomal aggregation pathways to immune-specialized sites, coupling substrate clearance to antigenic peptide production and enhancing CD8⁺ T cell engagement. Using a cellular model of aggregation-prone Tau, we show that BAG2 IDCs capture pathological Tau fibrils at ER–microtubule interfaces and process them into antigenic peptides, thereby reducing the abundance of the aggregation-prone PHF6 motif. We term this system the Proteostasis-Associated Immune Relay (PAIR), establishing IDCs as critical hubs with potential implications for multiple disease states.

2026-04-08 | GSE326781 | GEO

Enhancement of ubiquitination-dependent mitophagy by unconventionally-acting PROTACs

Project description:Enhancing mitophagy, a naturally-occurring cellular process for elimination of damaged mitochondria, holds great promise for the intervention of many human diseases. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that induce ubiquitination and subsequent proteasome-mediated degradation of a target protein through simultaneously binding to the target protein and an E3 ubiquitin ligase. However, the narrow cavity of the proteasome prevents the degradation of mitochondria. Here we show that the E3 ubiquitin ligase MAP3K1, when recruited to the outer mitochondria membrane (OMM) protein TSPO by our PROTAC-designed molecules (termed “mitophagy-enhancing chimeras”, or MECs), induced extensive K63 ubiquitination of TSPO and other OMM proteins, reminiscent of the PINK1-activated Parkin, without triggering proteasome-mediated degradation of TSPO. Aided by NBR1 and Nur77, this increased K63 ubiquitination of OMM proteins triggered mitophagy exclusively for damaged mitochondria, leading to improved mitochondria function and diminished cellular ROS. With the capability to enhance mitophagy at low nanomolar concentrations, MECs effectively inhibited NLRP3 inflammasome activation, abrogated acetaminophen-induced acute liver injury and mitigated high-fat diet-induced obesity in mice. Our work provided a proof-of-concept for developing unconventionally-acting PROTACs to achieve degradation of damaged mitochondria and possibly other organelles.

2024-02-08 | GSE255354 | GEO

The deubiquitinase OTULIN regulates tau expression in neurons

Project description:Degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system (UPS) and autophagy, which are impaired in Alzheimer’s disease (AD) and related tauopathies causing tau aggregation. Protein ubiquitination with linkage specificity determines the fate of proteins that can be either degradative or stabilization signals. While the linear M1-linked ubiquitination on protein aggregates is a signaling hub that recruits various ubiquitin-binding proteins for coordinated actions of protein aggregates turnover and inflammatory NF-kB activation, the deubiquitinase OTULIN counteracts with the M1-linked ubiquitin signaling. However, the exact role of OTULIN on tau aggregate clearance in AD is unknown. We did bulk RNA sequencing in wild-type and OTULIN knockout (by CRISPR-Cas9) SH-SY5Y human neuroblastoma cells. Our results showed a 14.39-fold down-regulation of tau mRNA levels and differential expression of many other genes associated with autophagy, the ubiquitin-proteasome system (UPS), NF-kB pathway, and RNA metabolism. Together, our results suggest for the first time a non-canonical function for OTULIN in regulating gene expression and RNA metabolism, which may have a significant pathogenic role in AD and related tauopathies.

2026-03-11 | GSE294134 | GEO

Transcriptional stress responses induced by compartment-targeted misfolding-prone proteins in Drosophila

Project description:Loss of proteostasis is an aging hallmark and the culprit of many age-related diseases. Different cell compartments experience distinctive challenges to maintain protein quality control but it remains underexplored how subcellular proteostasis is regulated by aging. Here, by targeting the misfolding_x0002_prone FlucDM luciferase to the cytoplasm, mitochondria, and nucleus, we have established transgenic sensors to examine subcellular proteostasis in Drosophila. Analysis of detergent-insoluble and -soluble levels of compartment-targeted FlucDM variants indicates that thermal stress, cold shock, and endocrine signaling differentially affect subcellular proteostasis during aging. Moreover, aggregation-prone proteins that cause different neurodegenerative diseases induce a diverse range of outcomes on FlucDM insolubility, suggesting that subcellular proteostasis is deranged in a disease-specific manner. Further analyses with FlucDM and mass spectrometry indicate that pathogenic tauV337M regulates in opposite manners the solubility of protein sets located in distinct organelles. Altogether, compartment-targeted FlucDM variants pinpoint a diverse modulation of subcellular proteostasis by aging regulators.

2024-09-30 | GSE243224 | GEO

The deubiquitinase OTULIN regulates tau expression in neurons [sAD2.1_WTC11_iPSNs]

Project description:Degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system (UPS) and autophagy, which are impaired in Alzheimer’s disease (AD) and related tauopathies causing tau aggregation. Protein ubiquitination with linkage specificity determines the fate of proteins that can be either degradative or stabilization signals. While the linear M1-linked ubiquitination on protein aggregates is a signaling hub that recruits various ubiquitin-binding proteins for coordinated actions of protein aggregates turnover and inflammatory NF-kB activation, the deubiquitinase OTULIN counteracts with the M1-linked ubiquitin signaling. However, the exact role of OTULIN on tau aggregate clearance in AD is unknown. We did bulk RNA sequencing in human inducible pluripotent stem cell (iPSC)-derived neurons (iPSNs) from a healthy control (WTC11) and an individual with late-onset sporadic AD (sAD2.1), which shows downregulation of ubiquitin ligase activating factors (MAGEA2B and MAGEA) and OTULIN long non-coding RNA (lncRNA-OTULIN) compared to healthy control WTC11 iPSNs. In sAD2.1 iPSNs, downregulated lncRNA-OTULIN is inversely correlated with increased levels of OTULIN protein and phosphorylated tau at p-S202/p-T205 (AT8), p-T231 (AT180), and p-S396/p-S404 (PHF-1). Loss of OTULIN deubiquitinase function using pharmacological inhibitor UC495 or CRISPR-Cas9-mediated OTULIN gene knockout causes a significant reduction of total tau and phosphory-lated tau at AT8 epitope in sAD2.1 iPSNs. Together, our results suggest for the first time a non-canonical function for OTULIN in regulating gene expression and RNA metabolism, which may have a significant pathogenic role in AD and related tauopathies.

2026-03-11 | GSE294290 | GEO

Hsp multichaperone complex buffers pathologically modified Tau

Project description:Alzheimer's disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70/Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70/Hsp90 machinery forming a 710 kDa client-loading complex. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on Tau’s aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperone/substrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70/Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70/Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative disorders.

2022-08-11 | PXD032037 | Pride

Gene expression data from cortex of 9 week old wild type, R6/2, HDAC4het and R6/2::HDAC4het mice

Project description:Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics. mRNA expression analysis was performed by microarray in 9 weeks old WT (n=9), R6/2 (n=9), HDAC4het (n=9) and Double R6/2::HDAC4het (n=10) mice. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

2014-10-10 | E-GEOD-38218 | biostudies-arrayexpress

Gene expression data from cortex of 15 week old wild type, R6/2, HDAC4het and R6/2::HDAC4het mice

Project description:Histone deacetylase (HDAC) 4 is a transcriptional repressor that contains a glutamine rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD), a protein folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion and transcriptional dysregulation. We found that HDAC4 interacts with huntingtin in a polyglutamine-length dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor co-ordination, neurological phenotypes and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for cytoplasmic aggregation in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation which may be amenable to small molecule therapeutics. mRNA expression analysis was performed by microarray in 15 weeks old WT (n=8), R6/2 (n=9), HDAC4het (n=8) and Double R6/2::HDAC4het (n=9) mice. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

2014-10-10 | E-GEOD-38219 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data