bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2023–04–09
fourteen papers selected by
Rich Giadone, Harvard University
  1. The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.
  2. Reversible protein assemblies in the proteostasis network in health and disease.
  3. Proteostasis networks in aging: novel insights from text-mining approaches.
  4. S100B chaperone multimers suppress the formation of oligomers during Aβ42 aggregation.
  5. Editorial: A focus on chaperone clients.
  6. Enhanced Degradation of Mutant C9ORF72-Derived Toxic Dipeptide Repeat Proteins by 20S Proteasome Activation Results in Restoration of Proteostasis and Neuroprotection.
  7. Editorial: Role of microglia autophagy in age-related neurodegenerative diseases.
  8. Transcriptomic reprogramming for neuronal age reversal.
  9. Heterogeneous aging across multiple organ systems and prediction of chronic disease and mortality.
  10. X-box Binding Protein 1: An Adaptor in the Pathogenesis of Atherosclerosis.
  11. Histone chaperones: A multinodal highway network inside the cell.
  12. MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
  13. Detrimental effects of soluble α-synuclein oligomers at excitatory glutamatergic synapses.
  14. Proteostasis modulation in germline missense von Hippel Lindau disease.
  1. Mol Ther. 2023 Apr 03. pii: S1525-0016(23)00161-2. [Epub ahead of print]
    The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.
    Claudia Duran-Aniotz, Natalia Poblete, Catalina Rivera-Krstulovic, Álvaro O Ardiles, Mei Li Díaz, Giovanni Tamburini, Carleen Mae P Sabusap, Yannis Gerakis, Felipe Cabral Miranda, Javier Diaz, Matias Fuentealba, Diego Arriagada, Ernesto Muñoz, Sandra Espinoza, Gabriela Martinez, Gabriel Quiroz, Danilo B Medinas, Darwin Contreras, Ricardo Piña, Mychael V Lourenco, Felipe C Ribeiro, Sergio T Ferreira, Carlos Rozas, Bernardo Morales, Lars Plate, Christian Gonzalez-Billault, Adrian G Palacios, Claudio Hetz.
      Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.
    DOI:  https://doi.org/10.1016/j.ymthe.2023.03.028
  2. Front Mol Biosci. 2023 ;10 1155521
    Reversible protein assemblies in the proteostasis network in health and disease.
    Verena Kohler, Claes Andréasson.
      While proteins populating their native conformations constitute the functional entities of cells, protein aggregates are traditionally associated with cellular dysfunction, stress and disease. During recent years, it has become clear that large aggregate-like protein condensates formed via liquid-liquid phase separation age into more solid aggregate-like particles that harbor misfolded proteins and are decorated by protein quality control factors. The constituent proteins of the condensates/aggregates are disentangled by protein disaggregation systems mainly based on Hsp70 and AAA ATPase Hsp100 chaperones prior to their handover to refolding and degradation systems. Here, we discuss the functional roles that condensate formation/aggregation and disaggregation play in protein quality control to maintain proteostasis and why it matters for understanding health and disease.
    Keywords:  Hsp100; Hsp70; aggregate; biomolecular condensate; degradation; disaggregation; phase separation; refolding
    DOI:  https://doi.org/10.3389/fmolb.2023.1155521
  3. Biogerontology. 2023 Apr 01.
    Proteostasis networks in aging: novel insights from text-mining approaches.
    Diogo Neves, Sara Duarte-Pereira, Sérgio Matos, Raquel M Silva.
      Aging is a topic of paramount importance in an increasingly elderly society and has been the focus of extensive research. Protein homeostasis (proteostasis) decline is a hallmark in aging and several age-related diseases, but which specific proteins and mechanisms are involved in proteostasis (de)regulation during the aging process remain largely unknown. Here, we used different text-mining tools complemented with protein-protein interaction data to address this complex topic. Analysis of the integrated protein interaction networks identified novel proteins and pathways associated to proteostasis mechanisms and aging or age-related disorders, indicating that this approach is useful to identify previously unknown links and for retrieving information of potential novel biomarkers or therapeutic targets.
    Keywords:  EGAS; Inflammasome; NAD metabolism; Protein aggregation; Protein–protein interactions
    DOI:  https://doi.org/10.1007/s10522-023-10027-0
  4. Front Neurosci. 2023 ;17 1162741
    S100B chaperone multimers suppress the formation of oligomers during Aβ42 aggregation.
    António J Figueira, Joana Saavedra, Isabel Cardoso, Cláudio M Gomes.
      Extracellular aggregation of the amyloid-β 1-42 (Aβ42) peptide is a major hallmark of Alzheimer's disease (AD), with recent data suggesting that Aβ intermediate oligomers (AβO) are more cytotoxic than mature amyloid fibrils. Understanding how chaperones harness such amyloid oligomers is critical toward establishing the mechanisms underlying regulation of proteostasis in the diseased brain. This includes S100B, an extracellular signaling Ca2+-binding protein which is increased in AD as a response to neuronal damage and whose holdase-type chaperone activity was recently unveiled. Driven by this evidence, we here investigate how different S100B chaperone multimers influence the formation of oligomers during Aβ42 fibrillation. Resorting to kinetic analysis coupled with simulation of AβO influx distributions, we establish that supra-stoichiometric ratios of dimeric S100B-Ca2+ drastically decrease Aβ42 oligomerization rate by 95% and AβO levels by 70% due to preferential inhibition of surface-catalyzed secondary nucleation, with a concomitant redirection of aggregation toward elongation. We also determined that sub-molar ratios of tetrameric apo-S100B decrease Aβ42 oligomerization influx down to 10%, while precluding both secondary nucleation and, more discreetly, fibril elongation. Coincidently, the mechanistic predictions comply with the independent screening of AβO using a combination of the thioflavin-T and X-34 fluorophores. Altogether, our findings illustrate that different S100B multimers act as complementary suppressors of Aβ42 oligomerization and aggregation, further underpinning their potential neuroprotective role in AD.
    Keywords:  aggregation kinetics and mechanism; amyloid beta (1–42); amyloid-β oligomers; molecular chaperones; protein aggregation
    DOI:  https://doi.org/10.3389/fnins.2023.1162741
  5. Front Mol Biosci. 2023 ;10 1180739
    Editorial: A focus on chaperone clients.
    Amnon Horovitz, Abdussalam Azem.
      
    Keywords:  ClpP; GroEL; chaperones; chaperonin; hsp70; protein folding
    DOI:  https://doi.org/10.3389/fmolb.2023.1180739
  6. ACS Chem Neurosci. 2023 Apr 04.
    Enhanced Degradation of Mutant C9ORF72-Derived Toxic Dipeptide Repeat Proteins by 20S Proteasome Activation Results in Restoration of Proteostasis and Neuroprotection.
    Allison S Vanecek, Jelena Mojsilovic-Petrovic, Robert G Kalb, Jetze J Tepe.
      A hexanucleotide repeat expansion (HRE) in an intron of gene C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. The HRE undergoes noncanonical translation (repeat-associated non-ATG translation) resulting in the production of five distinct dipeptide repeat (DPR) proteins. Arginine-rich DPR proteins have shown to be toxic to motor neurons, and recent evidence suggests this toxicity is associated with disruption of the ubiquitin-proteasome system. Here we report the ability of known 20S proteasome activator, TCH-165, to enhance the degradation of DPR proteins and overcome proteasome impairment evoked by DPR proteins. Furthermore, the 20S activator protects rodent motor neurons from DPR protein toxicity and restores proteostasis in cortical neuron cultures. This study suggests that 20S proteasome enhancers may have therapeutic efficacy in neurodegenerative diseases that display proteostasis defects.
    Keywords:  Amyotrophic lateral sclerosis; DPR proteins; UPS impairment; frontotemporal dementia; neurodegenerative diseases; neuroprotection; proteasome; proteostasis
    DOI:  https://doi.org/10.1021/acschemneuro.2c00732
  7. Front Aging Neurosci. 2023 ;15 1175935
    Editorial: Role of microglia autophagy in age-related neurodegenerative diseases.
    Zihua Wang.
      
    Keywords:  autophagy; drug delivery; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2023.1175935
  8. Hum Genet. 2023 Apr 01.
    Transcriptomic reprogramming for neuronal age reversal.
    Alexandru M Plesa, Michael Shadpour, Ed Boyden, George M Church.
      Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of death worldwide, and they are becoming a pressing problem for our society. To address this global challenge, there is a need for novel, safe, and effective rejuvenation therapies aimed at reversing age-related phenotypes and improving human health. With gene expression being a key determinant of cell identity and function, and in light of recent studies reporting rejuvenation effects through genetic perturbations, we propose an age reversal strategy focused on reprogramming the cell transcriptome to a youthful state. To this end, we suggest using transcriptomic data from primary human cells to predict rejuvenation targets and develop high-throughput aging assays, which can be used in large perturbation screens. We propose neural cells as particularly relevant targets for rejuvenation due to substantial impact of neurodegeneration on human frailty. Of all cell types in the brain, we argue that glutamatergic neurons, neuronal stem cells, and oligodendrocytes represent the most impactful and tractable targets. Lastly, we provide experimental designs for anti-aging reprogramming screens that will likely enable the development of neuronal age reversal therapies, which hold promise for dramatically improving human health.
    DOI:  https://doi.org/10.1007/s00439-023-02529-1
  9. Nat Med. 2023 Apr 06.
    Heterogeneous aging across multiple organ systems and prediction of chronic disease and mortality.
    Ye Ella Tian, Vanessa Cropley, Andrea B Maier, Nicola T Lautenschlager, Michael Breakspear, Andrew Zalesky.
      Biological aging of human organ systems reflects the interplay of age, chronic disease, lifestyle and genetic risk. Using longitudinal brain imaging and physiological phenotypes from the UK Biobank, we establish normative models of biological age for three brain and seven body systems. Here we find that an organ's biological age selectively influences the aging of other organ systems, revealing a multiorgan aging network. We report organ age profiles for 16 chronic diseases, where advanced biological aging extends from the organ of primary disease to multiple systems. Advanced body age associates with several lifestyle and environmental factors, leukocyte telomere lengths and mortality risk, and predicts survival time (area under the curve of 0.77) and premature death (area under the curve of 0.86). Our work reveals the multisystem nature of human aging in health and chronic disease. It may enable early identification of individuals at increased risk of aging-related morbidity and inform new strategies to potentially limit organ-specific aging in such individuals.
    DOI:  https://doi.org/10.1038/s41591-023-02296-6
  10. Aging Dis. 2023 Apr 01. 14(2): 350-369
    X-box Binding Protein 1: An Adaptor in the Pathogenesis of Atherosclerosis.
    Tao Wang, Jia Zhou, Xiao Zhang, Yujie Wu, Kehan Jin, Yilin Wang, Ran Xu, Ge Yang, Wenjing Li, Liqun Jiao.
      Atherosclerosis (AS), the formation of fibrofatty lesions in the vessel wall, is the primary cause of heart disease and stroke and is closely associated with aging. Disrupted metabolic homeostasis is a primary feature of AS and leads to endoplasmic reticulum (ER) stress, which is an abnormal accumulation of unfolded proteins. By orchestrating signaling cascades of the unfolded protein response (UPR), ER stress functions as a double-edged sword in AS, where adaptive UPR triggers synthetic metabolic processes to restore homeostasis, whereas the maladaptive response programs the cell to the apoptotic pathway. However, little is known regarding their precise coordination. Herein, an advanced understanding of the role of UPR in the pathological process of AS is reviewed. In particular, we focused on a critical mediator of the UPR, X-box binding protein 1 (XBP1), and its important role in balancing adaptive and maladaptive responses. The XBP1 mRNA is processed from the unspliced isoform (XBP1u) to the spliced isoform of XBP1 (XBP1s). Compared with XBP1u, XBP1s predominantly functions downstream of inositol-requiring enzyme-1α (IRE1α) and transcript genes involved in protein quality control, inflammation, lipid metabolism, carbohydrate metabolism, and calcification, which are critical for the pathogenesis of AS. Thus, the IRE1α/XBP1 axis is a promising pharmaceutical candidate against AS.
    Keywords:  IRE1α; XBP1; atherosclerosis; endoplasmic reticulum stress; unfolded protein response
    DOI:  https://doi.org/10.14336/AD.2022.0824
  11. Mol Cell. 2023 Apr 06. pii: S1097-2765(23)00161-2. [Epub ahead of print]83(7): 1024-1026
    Histone chaperones: A multinodal highway network inside the cell.
    Zhiming Li, Zhiguo Zhang.
      Histone chaperones participate in the biogenesis, transportation, and deposition of histones. They contribute to processes impacted by nucleosomes including DNA replication, transcription, and epigenetic inheritance. In this issue, Carraro et al.1 reveal an interconnected chaperone network and a surprising function of histone chaperone DAXX in de novo deposition of H3.3K9me3.
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.004
  12. Autophagy Rep. 2022 ;1(1): 210-213
    MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
    Priyanka Gajwani, Jalees Rehman.
      Differentiating stem cells must adapt their mitochondrial metabolism to fit the needs of the mature differentiated cell. In a recent study, we observed that during differentiation to an endothelial phenotype, pluripotent stem cell mitochondria are removed by mitophagy, triggering compensatory mitochondrial biogenesis to replenish the mitochondrial pool. We identified the mitochondrial phosphatase PGAM5 as the link between mitophagy and transcription of the mitochondrial biogenesis regulator PPARGC1A/PGC1α in the nucleus. Swapping of mitochondria through the coupled processes of mitophagy and mitochondrial biogenesis lead to enhanced metabolic reprogramming in the differentiated cell.
    Keywords:  CTNNB1/β-catenin; PINK1; PPARGC1A/PGC1α; differentiation; endothelium; mitochondrial biogenesis; mitofusin 2; mitophagy; stem cells
    DOI:  https://doi.org/10.1080/27694127.2022.2071549
  13. Front Aging Neurosci. 2023 ;15 1152065
    Detrimental effects of soluble α-synuclein oligomers at excitatory glutamatergic synapses.
    Elena Ferrari, Michela Salvadè, Elisa Zianni, Marta Brumana, Monica DiLuca, Fabrizio Gardoni.
       Introduction: Oligomeric and fibrillar species of the synaptic protein α-synuclein are established key players in the pathophysiology of Parkinson's disease and other synucleinopathies. Increasing evidence in the literature points to prefibrillar oligomers as the main cytotoxic species driving dysfunction in diverse neurotransmitter systems even at early disease stages. Of note, soluble oligomers have recently been shown to alter synaptic plasticity mechanisms at the glutamatergic cortico-striatal synapse. However, the molecular and morphological detrimental events triggered by soluble α-synuclein aggregates that ultimately lead to excitatory synaptic failure remain mostly elusive.
    Methods: In the present study, we aimed to clarify the effects of soluble α-synuclein oligomers (sOligo) in the pathophysiology of synucleinopathies at cortico-striatal and hippocampal excitatory synapses. To investigate early defects of the striatal synapse in vivo, sOligo were inoculated in the dorsolateral striatum of 2-month-old wild-type C57BL/6J mice, and molecular and morphological analyses were conducted 42 and 84 days post-injection. In parallel, primary cultures of rat hippocampal neurons were exposed to sOligo, and molecular and morphological analyses were performed after 7 days of treatment.
    Results: In vivo sOligo injection impaired the post-synaptic retention of striatal ionotropic glutamate receptors and decreased the levels of phosphorylated ERK at 84 days post-injection. These events were not correlated with morphological alterations at dendritic spines. Conversely, chronic in vitro administration of sOligo caused a significant decrease in ERK phosphorylation but did not significantly alter post-synaptic levels of ionotropic glutamate receptors or spine density in primary hippocampal neurons.
    Conclusion: Overall, our data indicate that sOligo are involved in pathogenic molecular changes at the striatal glutamatergic synapse, confirming the detrimental effect of these species in an in vivo synucleinopathy model. Moreover, sOligo affects the ERK signaling pathway similarly in hippocampal and striatal neurons, possibly representing an early mechanism that anticipates synaptic loss.
    Keywords:  NMDA–receptor; Parkinson’s disease; dendritic spine; glutamate; mice
    DOI:  https://doi.org/10.3389/fnagi.2023.1152065
  14. Clin Cancer Res. 2023 Apr 05. pii: CCR-22-3651. [Epub ahead of print]
    Proteostasis modulation in germline missense von Hippel Lindau disease.
    Prashant Chittiboina, Debjani Mandal, Alejandro Bugarini, David T Asuzu, Dustin Mullaney, Panagiotis Mastorakos, Stefan Stoica, Reinier Alvarez, Gretchen Scott, Dragan Maric, Abdel Elkahloun, Zhengping Zhuang, Emily Y Chew, Chunzhang Yang, Marston Linehan, Russell R Lonser.
       PURPOSE: Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation/progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in pre-clinical models. We asked if short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in germline missense VHL patients.
    EXPERIMENTAL DESIGN: We administered oral vorinostat to seven subjects (aged 46.0±14.5 years) and then removed symptomatic hemangioblastomas surgically (clinicaltrials.gov identifier NCT02108002).
    RESULTS: Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared to untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream HIF effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in-vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of pro-tumorigenic pathways with single nucleus transcriptomic profiling.
    CONCLUSIONS: We found that oral vorinostat treatment in VHL patients with germline missense mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3651
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