PH modulation restores proteostasis and extend lifespan in a yeast model of Huntington’s Disease [polyQ]
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ABSTRACT:
PROVIDER: PRJNA1262381 | ENA |
REPOSITORIES: ENA
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Project description:Loss of proteostasis is a hallmark of the aging process and is associated with the onset of several neurodegenerative diseases, including Huntington’s Disease (HD) where aberrant polyglutamine (polyQ) expanded Huntingtin aggregates into insoluble inclusions bodies (IBs) associated with toxicity in neuronal cells. In yeast, chronological lifespan (CLS) assays are used to model aging of non-dividing cells such as neurons. During CLS, acidification of the culture media due accumulation of acetic acid is one of the major cell extrinsic factors responsible for cell death. Thus, buffering media pH to prevent acidification significantly extends longevity. Here, we found that cells expressing pathogenic polyQ expansions display increased sensitivity to acetic acid and shortened CLS. Buffering media pH promotes both polyQ aggregation into IBs and longevity. We found that growth at higher pH induces the activation of heat shock response (HSR) in young cells. Such hormetic HSR activation subsequently allowed aged cells to mount a proper HSR in response to stresses such as heat shock or polyQ misfolding, leading to lifespan extension. Thus, our study provides new insight into how pH can promote proteotoxic stress resistance and longevity.
2025-09-06 | GSE297008 | GEO
Project description:Loss of proteostasis is a hallmark of the aging process and is associated with the onset of several neurodegenerative diseases, including Huntington’s Disease (HD) where aberrant polyglutamine (polyQ) expanded Huntingtin aggregates into insoluble inclusions bodies (IBs) associated with toxicity in neuronal cells. In yeast, chronological lifespan (CLS) assays are used to model aging of non-dividing cells such as neurons. During CLS, acidification of the culture media due accumulation of acetic acid is one of the major cell extrinsic factors responsible for cell death. Thus, buffering media pH to prevent acidification significantly extends longevity. Here, we found that cells expressing pathogenic polyQ expansions display increased sensitivity to acetic acid and shortened CLS. Buffering media pH promotes both polyQ aggregation into IBs and longevity. We found that growth at higher pH induces the activation of heat shock response (HSR) in young cells. Such hormetic HSR activation subsequently allowed aged cells to mount a proper HSR in response to stresses such as heat shock or polyQ misfolding, leading to lifespan extension. Thus, our study provides new insight into how pH can promote proteotoxic stress resistance and longevity.
2025-09-06 | GSE297007 | GEO
Project description:pH modulation restores proteostasis and extend lifespan in a yeast model of Huntington’s Disease [pH]
| PRJNA1262369 | ENA
Project description:Pluripotent stem cells undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome, a capacity that demands a highly induced proteostasis network. As such, induced pluripotent stem cells (iPSCs) suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington’s disease (HD). Here we show that proteasome activity determines HTT levels, preventing the accumulation of polyQ-expanded aggregates in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit intrinsic high levels of UBR5, an E3 ubiquitin ligase that we find required for proteasomal degradation of both normal and mutant HTT. When UBR5 fails to monitor HTT proteostasis, the concomitant up-regulation of HTT expression particularly results in polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens protein aggregation and neurotoxicity in polyQ-expanded invertebrate models. Notably, ectopic expression of UBR5 is sufficient to induce polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD cell models. However, UBR5 is dispensable for the proteostasis of other aggregation-prone proteins linked with Machado-Joseph disease or amyotrophic lateral sclerosis in iPSCs. Besides its role in HTT regulation, we find that intrinsic high levels of UBR5 also determine the global proteostatic ability of iPSCs preventing aggresome formation, suggesting a role in the control of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a central component of super-vigilant proteostasis of iPSCs with the potential to correct proteostatic deficiencies in HD.
2018-06-14 | PXD009803 | Pride
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
Project description:The amplification of a CAG repeat in the gene coding for huntingtin (HTT) leads to Huntington’s disease (HD). At the protein level, this translates into the expansion of a poly-glutamine (polyQ) stretch in the HTT N-terminus, which renders HTT aggregation-prone by unknown mechanisms. Here we investigate the effects of polyQ expansion on the HTT-HAP40 complex, where HTT structure is substantially stabilized. Surprisingly, our biophysical, cryo-EM and crosslinking mass spectrometry experiments reveal no major changes between 17QHTT-HAP40 (wild type), 46QHTT-HAP40 (typical polyQ length in HD patients) and 128QHTT-HAP40 (extreme polyQ length). Thus, the proposed destabilizing effect of HTT polyQ expansion may not suffice to alter the HTT-HAP40 complex, suggesting that polyQ expansion does not have a major global effect on HTT structure.
2021-03-19 | PXD018451 | Pride
Project description:Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
| PRJNA780423 | ENA
Project description:Manifestation of aggregate pathology in Huntington’s disease is thought to be facilitated by a preferential vulnerability of affected brain cells to age-dependent proteostatic decline. To understand how specific cellular backgrounds may facilitate pathologic aggregation, we utilized the yeast model in which polyQ-expanded Huntingtin forms aggregates only when the endogenous prion-forming protein Rnq1 is in its amyloid-like prion [PIN+] conformation. We employed optogenetic clustering of polyQ protein as an orthogonal method to induce polyQ aggregation in prion-free [pin-] cells. Optogenetic aggregation circumvented the prion requirement for the formation of detergent-resistant polyQ inclusions, but bypassed the formation of toxic polyQ oligomers, which accumulated specifically in [PIN+] cells. Reconstitution of aggregation in vitro suggested that these polyQ oligomers formed through direct templating on Rnq1 prions. These findings shed light on the mechanism of prion-mediated formation of oligomers, which may play a role in triggering polyQ pathology in the patient brain.
2022-10-21 | PXD031337 | Pride
Project description:Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here we define a molecular pathway through which recombinant interleukin-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activates NADPH Oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1 dependent anti-inflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.
2021-11-27 | GSE188809 | GEO
Project description:Protein aggregation is a hallmark of many neurodegenerative diseases. In order to cope with misfolding and aggregation, cells have evolved an elaborate network of molecular chaperones, composed of different families. But while chaperoning mechanisms for different families are well established, functional and regulatory diversification within chaperone families is still largely a mystery. Here we decided to explore chaperone functional diversity, through the lens of pathological aggregation. We revealed that different naturally-occurring isoforms of DNAJ chaperones showed differential effects on different types of aggregates. We performed a chaperone screen for modulators of two neurodegeneration-related aggregating proteins, the Huntington’s disease-related HTT-polyQ, and the ALS-related mutant FUS (mutFUS). The screen identified known modulators of HTT-polyQ aggregation, confirming the validity of our approach. Surprisingly, modulators of mutFUS aggregation were completely different than those of HTT-polyQ. Interestingly, different naturally-occurring isoforms of DNAJ chaperones had opposing effects on HTT-polyQ vs. mutFUS aggregation. We identified a complex of the full length (FL) DNAJB14 and DNAJB12 isoforms which substantially alleviated mutFUS aggregation, in an HSP70-dependent manner. Their naturally occurring short isoforms were unable to form the complex, nor to interact with HSP70, and lost their ability to reduce mutFUS aggregation. In contrast, the short isoform of DNAJB12 significantly alleviated HTT-polyQ aggregation, while DNAJB12-FL aggravated HTT-polyQ aggregation. Finally, we demonstrated that full-length DNAJB14 ameliorated mutFUS aggregation compared to DNAJB14-short in primary neurons. Together, our data unraveled distinct molecular properties required for aggregation protection in different neurodegenerative diseases, and revealed a new layer of complexity of the chaperone network elicited by naturally occurring J-protein isoforms, highlighting functional diversity among the DNAJ family.
2021-12-07 | GSE165317 | GEO