bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023‒02‒19
fourteen papers selected by
Rich Giadone
Harvard University
  1. Extensive accumulation of misfolded protein aggregates during natural aging and senescence.
  2. A Year at the Forefront of Proteostasis and Aging.
  3. Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes.
  4. Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1-mediated heat shock response.
  5. Controlling htt protein aggregation to assess toxicity in Caenorhabditis elegans.
  6. The molecular basis for the synergistic aggregation of tau by alpha-synuclein.
  7. SQSTM1 facilitates oocyte maturation through inducing ACLY degradation mediated by selective autophagy.
  8. Coupling of autophagy and the mitochondrial intrinsic apoptosis pathway modulates proteostasis and ageing in Caenorhabditis elegans.
  9. Neurodegeneration cell per cell.
  10. Neuronal endoplasmic reticulum architecture and roles in axonal physiology.
  11. Structure-based discovery of small molecules that disaggregate amyloid fibrils from post-mortem Alzheimer's and Parkinson's brains.
  12. The impact of endoplasmic reticulum morphology on IRE1 protein clustering.
  13. Precise mapping of molecular and cellular brain changes in Alzheimer's disease.
  14. The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept.
  1. Front Aging Neurosci. 2022 ;14 1090109
    Extensive accumulation of misfolded protein aggregates during natural aging and senescence.
    Karina Cuanalo-Contreras, Jonathan Schulz, Abhisek Mukherjee, Kyung-Won Park, Enrique Armijo, Claudio Soto.
      Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells, Caenorhabditis elegans, and mouse tissues collected at different times from youth to old age. Our results show a significant accumulation of misfolded protein aggregates in aged samples as compared to young materials. Indeed, aged samples have between 1.3 and 2.5-fold (depending on the biological system) higher amount of insoluble proteins than young samples. These insoluble proteins exhibit the typical characteristics of disease-associated aggregates, including insolubility in detergents, protease resistance, and staining with amyloid-binding dye as well as accumulation in aggresomes. We identified the main proteins accumulating in the aging brain using proteomic studies. These results show that the aged brain contain large amounts of misfolded and likely non-functional species of many proteins, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. Our findings reveal a putative role for protein misfolding and aggregation in aging.
    Keywords:  aggresomes; aging; amyloid; prions; protein misfolding; proteostasis; senescence
    DOI:  https://doi.org/10.3389/fnagi.2022.1090109
  2. Biol Open. 2023 Feb 15. pii: bio059750. [Epub ahead of print]12(2):
    A Year at the Forefront of Proteostasis and Aging.
    Maximilian A Thompson, Evandro A De-Souza.
      During aging, animals experience a decline in proteostasis activity, including loss of stress-response activation, culminating in the accumulation of misfolded proteins and toxic aggregates, which are causal in the onset of some chronic diseases. Finding genetic and pharmaceutical treatments that can increase organismal proteostasis and lengthen life is an ongoing goal of current research. The regulation of stress responses by cell non-autonomous mechanisms appears to be a potent way to impact organismal healthspan. In this Review, we cover recent findings in the intersection of proteostasis and aging, with a special focus on articles and preprints published between November 2021 and October 2022. A significant number of papers published during this time increased our understanding of how cells communicate with each other during proteotoxic stress. Finally, we also draw attention to emerging datasets that can be explored to generate new hypotheses that explain age-related proteostasis collapse.
    Keywords:  Cell non-autonomous response; Heat shock response; Longevity; Protein homeostasis; UPR
    DOI:  https://doi.org/10.1242/bio.059750
  3. bioRxiv. 2023 Feb 09. pii: 2023.02.09.527889. [Epub ahead of print]
    Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes.
    Anit Shah, Ian Huck, Kaylia Duncan, Erica R Gansemer, Udayan Apte, Mark A Stamnes, D Thomas Rutkowski.
      In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Several pathways potentially link HNF4α to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4α activity is linked to hepatic ER homeostasis through multiple mechanisms.
    DOI:  https://doi.org/10.1101/2023.02.09.527889
  4. PLoS Biol. 2023 Feb 13. 21(2): e3001605
    Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1-mediated heat shock response.
    Jay Miles, Sarah Townend, Dovilė Milonaitytė, William Smith, Francesca Hodge, David R Westhead, Patricija van Oosten-Hawle.
      Organismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the Caenorhabditis elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here, we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress signaling from the intestine to the muscle is regulated. We find that the TCS-mediated "gut-to-muscle" induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of "inter-tissue" stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1-mediated heat shock response is switched off upon TCS activation, in favor of an intercellular stress-signaling route to safeguard survival.
    DOI:  https://doi.org/10.1371/journal.pbio.3001605
  5. Biophys J. 2023 Feb 10. pii: S0006-3495(22)01464-3. [Epub ahead of print]122(3S1): 63a
    Controlling htt protein aggregation to assess toxicity in Caenorhabditis elegans.
    Ephraim C Ezeigbo, Justin A Legleiter.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.548
  6. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02130-0. [Epub ahead of print]122(3S1): 200a-201a
    The molecular basis for the synergistic aggregation of tau by alpha-synuclein.
    Jennifer Ramirez, E James Petersson, Elizabeth Rhoades.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1214
  7. Cell Cycle. 2023 Feb 14. 1-3
    SQSTM1 facilitates oocyte maturation through inducing ACLY degradation mediated by selective autophagy.
    Heide Schatten.
      Selective autophagy specifically eliminates certain intracellular substrates through the autophagy pathway. Organelles and aggregation-prone proteins can be degraded through the autophagy receptor protein SQSTM1/p62, which renders them a promising therapeutic approach against infertility. He et al. demonstrate that blocking of autophagy in cumulus granulosa cells can directly attenuate citrate levels and in turn affect oocyte maturation quality. Further findings show that SQSTM1 connects K63-polyubiquitinated ACLY (ATP citrate lyase) during the process of selective autophagic degradation, which further compromises the homeostasis of citrate. Therefore, the quality of oocyte meiotic maturation can be evaluated by the levels of selective autophagy in cumulus granulosa cells.
    Keywords:  ACLY; Sqstm1/P62; citrate; meiotic resumption; selective autophagy
    DOI:  https://doi.org/10.1080/15384101.2023.2176673
  8. Cell Death Dis. 2023 Feb 11. 14(2): 110
    Coupling of autophagy and the mitochondrial intrinsic apoptosis pathway modulates proteostasis and ageing in Caenorhabditis elegans.
    Christina Ploumi, Emmanouil Kyriakakis, Nektarios Tavernarakis.
      Mitochondria preserve metabolic homeostasis and integrate stress signals, to trigger cytoprotective, or cell death pathways. Mitochondrial homeostasis and function decline with age. The mechanisms underlying the deterioration of mitochondrial homeostasis during ageing, or in age-associated pathologies, remain unclear. Here, we show that CISD-1, a mitochondrial iron-sulfur cluster binding protein, implicated in the pathogenesis of Wolfram neurodegenerative syndrome type 2, modulates longevity in the nematode Caenorhabditis elegans by engaging autophagy and the mitochondrial intrinsic apoptosis pathway. The anti-apoptotic protein CED-9 is the downstream effector that mediates CISD-1-dependent effects on proteostasis, neuronal integrity and lifespan. Moreover, intracellular iron abundance is critical for CISD-1 function, since mild iron supplementation is sufficient to decelerate ageing and partly ameliorate the disturbed mitochondrial bioenergetics and proteostasis of CISD-1 deficient animals. Our findings reveal that CISD-1 serves as a mechanistic link between autophagy and the apoptotic pathway in mitochondria to differentially modulate organismal proteostasis and ageing, and suggest novel approaches which could facilitate the treatment of Wolfram Syndrome or related diseases.
    DOI:  https://doi.org/10.1038/s41419-023-05638-x
  9. Neuron. 2023 Feb 07. pii: S0896-6273(23)00064-8. [Epub ahead of print]
    Neurodegeneration cell per cell.
    Sriram Balusu, Roman Praschberger, Elsa Lauwers, Bart De Strooper, Patrik Verstreken.
      The clinical definition of neurodegenerative diseases is based on symptoms that reflect terminal damage of specific brain regions. This is misleading as it tells little about the initial disease processes. Circuitry failures that underlie the clinical symptomatology are themselves preceded by clinically mostly silent, slowly progressing multicellular processes that trigger or are triggered by the accumulation of abnormally folded proteins such as Aβ, Tau, TDP-43, and α-synuclein, among others. Methodological advances in single-cell omics, combined with complex genetics and novel ways to model complex cellular interactions using induced pluripotent stem (iPS) cells, make it possible to analyze the early cellular phase of neurodegenerative disorders. This will revolutionize the way we study those diseases and will translate into novel diagnostics and cell-specific therapeutic targets, stopping these disorders in their early track before they cause difficult-to-reverse damage to the brain.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; neurodegeneration; single-cell sequencing
    DOI:  https://doi.org/10.1016/j.neuron.2023.01.016
  10. Mol Cell Neurosci. 2023 Feb 11. pii: S1044-7431(23)00016-7. [Epub ahead of print] 103822
    Neuronal endoplasmic reticulum architecture and roles in axonal physiology.
    Klaas Yperman, Marijn Kuijpers.
      The endoplasmic reticulum (ER) is the largest membrane compartment within eukaryotic cells and is emerging as a key coordinator of many cellular processes. The ER can modulate local calcium fluxes and communicate with other organelles like the plasma membrane. The importance of ER in neuronal processes such as neurite growth, axon repair and neurotransmission has recently gained much attention. In this review, we highlight the importance of the ER tubular network in axonal homeostasis and discuss how the generation and maintenance of the thin tubular ER network in axons and synapses, requires a cooperative effort of ER-shaping proteins, cytoskeleton and autophagy processes.
    Keywords:  ER-phagy; Endoplasmic reticulum; Neuron; Neurotransmission; Synapse
    DOI:  https://doi.org/10.1016/j.mcn.2023.103822
  11. Biophys J. 2023 Feb 10. pii: S0006-3495(22)02679-0. [Epub ahead of print]122(3S1): 314a
    Structure-based discovery of small molecules that disaggregate amyloid fibrils from post-mortem Alzheimer's and Parkinson's brains.
    David S Eisenberg.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.1763
  12. Biophys J. 2023 Feb 10. pii: S0006-3495(22)03632-3. [Epub ahead of print]122(3S1): 510a
    The impact of endoplasmic reticulum morphology on IRE1 protein clustering.
    Liam Kischuck, Aidan Brown.
      
    DOI:  https://doi.org/10.1016/j.bpj.2022.11.2716
  13. Nat Neurosci. 2023 Feb 14.
    Precise mapping of molecular and cellular brain changes in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s41593-023-01254-2
  14. J Alzheimers Dis Rep. 2023 ;7(1): 21-35
    The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept.
    Vladimir Volloch, Sophia Rits-Volloch.
      Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimer's disease (AD) is driven by intraneuronal amyloid-β (iAβ) and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates, upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway, triggering a devastating second stage resulting in neuronal death. While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intra- rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD. Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious "substance X" (sX) which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.
    Keywords:  Age-related cognitive decline; Alzheimer’s disease; Amyloid Cascade Hypothesis 2.0; BACE1 and BACE2 activators; amyloid-β protein precursor; intraneuronal amyloid-β
    DOI:  https://doi.org/10.3233/ADR-220079
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