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:Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA-binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, are essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.
2026-05-15 | GSE294929 | GEO
Project description:Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA-binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, are essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.
2026-05-15 | GSE291671 | GEO
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:Huntington’s disease (HD) is an incurable, neurodegenerative disorder. While the causative mutation – CAG expansions within the coding region of the Huntingtin (HTT) gene – has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding. These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. To ask whether IBs are protective or harmful in human neuronal cells, and to elucidate the pathological pathways involved in polyQ IB formation, we developed an iPSC-based human neuronal models for polyQ-related disorders. We ectopically expressed the first 21 exons of the HTT gene, containing either 18Q or 105Q fused with GFP in HD patient-derived iPSCs containing 180Q or their isogenic corrected cells, respectively, differentiated them into neuronal progenitor cells (NPCs), and enriched for a pure population of polyQ IBs-containing cells (IB+). Comparing gene expression profiles between IB+ and IB- NPCs, growing side-by-side, in both systems, we identified ATF3 as responsible for inducing neuroinflammatory genes specifically in IB+ cells. ChIP-seq for ATF3 confirmed direct binding at their promoters, exclusively in IB+ NPCs. Remarkably, knocking out (KO) ATF3 completely prevented polyQ-IB formation in NPCs and rendered the cells more vulnerable to induced stress. Finally, using time-lapse imaging comparing cell death in IB+ and IB- NPCs, we demonstrate that polyQ IBs have a significant protective effect. Taken together, our results highlight ATF3’s role in polyQ IB formation in human NPCs, acting as an activator of inflammatory genes, and demonstrate that polyQ IBs protect cells from stress-induced death.
2026-04-01 | GSE285810 | GEO
Project description:Huntington’s disease (HD) is an incurable, neurodegenerative disorder. While the causative mutation – CAG expansions within the coding region of the Huntingtin (HTT) gene – has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding. These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. To ask whether IBs are protective or harmful in human neuronal cells, and to elucidate the pathological pathways involved in polyQ IB formation, we developed an iPSC-based human neuronal models for polyQ-related disorders. We ectopically expressed the first 21 exons of the HTT gene, containing either 18Q or 105Q fused with GFP in HD patient-derived iPSCs containing 180Q or their isogenic corrected cells, respectively, differentiated them into neuronal progenitor cells (NPCs), and enriched for a pure population of polyQ IBs-containing cells (IB+). Comparing gene expression profiles between IB+ and IB- NPCs, growing side-by-side, in both systems, we identified ATF3 as responsible for inducing neuroinflammatory genes specifically in IB+ cells. ChIP-seq for ATF3 confirmed direct binding at their promoters, exclusively in IB+ NPCs. Remarkably, knocking out (KO) ATF3 completely prevented polyQ-IB formation in NPCs and rendered the cells more vulnerable to induced stress. Finally, using time-lapse imaging comparing cell death in IB+ and IB- NPCs, we demonstrate that polyQ IBs have a significant protective effect. Taken together, our results highlight ATF3’s role in polyQ IB formation in human NPCs, acting as an activator of inflammatory genes, and demonstrate that polyQ IBs protect cells from stress-induced death.
2026-04-01 | GSE285808 | GEO